Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Adolescent maturation of dorsolateral prefrontal cortex glutamate:GABA and cognitive function is supported by dopamine-related neurobiology

Molecular Psychiatry volume 30, pages 2558–2572 (2025)Cite this article

Subjects

Abstract

Developmental changes in prefrontal cortex (PFC) excitatory (glutamatergic, Glu) and inhibitory (gamma- aminobutryic acid, GABA) neurotransmitter balance (E:I) have been identified during human adolescence, potentially reflecting a critical period of plasticity that supports the maturation of PFC-dependent cognition. Animal models implicate increases in dopamine (DA) in regulating changes in PFC E:I during critical periods of development, however, mechanistic relationships between DA and E:I have not been studied in humans. Here, we used high field (7T) echo planar imaging (EPI) in combination with Magnetic Resonance Spectroscopic Imaging (MRSI) to assess the role of basal ganglia tissue iron—reflecting DA neurophysiology—in longitudinal trajectories of dorsolateral PFC Glu, GABA, and their relative levels (Glu:GABA) and working memory performance from adolescence to adulthood in 153 participants (ages 10–32 years old, 1–3 visits, 272 visits total). Using generalized additive mixed models (GAMMs) that capture linear and non-linear developmental processes, we show that basal ganglia tissue iron increases during adolescence, and Glu:GABA is biased towards heightened Glu relative to GABA early in adolescence, decreasing into adulthood. Critically, variation in basal ganglia tissue iron was linked to different age-related trajectories in Glu:GABA and working memory. Specifically, individuals with higher levels of tissue iron showed a greater degree of age-related declines in Glu and Glu:GABA, resulting in lower Glu relative to GABA (i.e., higher GABA relative to Glu) in young adulthood. Variation in tissue iron additionally moderated working memory trajectories, as higher levels of tissue iron were associated with steeper age-related improvements and better performance into adulthood. Our results provide novel evidence for a model of critical period plasticity whereby individual differences in DA may be involved in fine-tuning PFC E:I and PFC-dependent cognitive function at a critical transition from adolescence into adulthood.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Study methods.
Fig. 2: Developmental Changes in Neurotransmitter Concentrations.
Fig. 3: Developmental interactions between nT2*w estimates of DA neurophysiology and DLPFC metabolites.
Fig. 4: Developmental interactions between nT2*w estimates of DA neurophysiology and working memory performance assessed using the MGS.

Similar content being viewed by others

Data availability

Data and analysis code will be made available upon request.

Code availability

Data and analysis code will be made available upon request.

References

  1. Blakemore SJ, Mills KL. Is adolescence a sensitive period for sociocultural processing? Annu Rev Psychol. 2014;65:187–207.

    Article  PubMed  Google Scholar 

  2. Larsen B, Luna B. Adolescence as a neurobiological critical period for the development of higher-order cognition. Neurosci Biobehav Rev. 2018;94:179–95.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Luna B, Marek S, Larsen B, Tervo-Clemmens B, Chahal R. An integrative model of the maturation of cognitive control. Annu Rev Neurosci. 2015;38:151–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tervo-Clemmens B, Calabro FJ, Parr AC, Fedor J, Foran W, Luna B. A canonical trajectory of executive function maturation from adolescence to adulthood. Nat Commun. 2023;14:6922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, et al. Dynamic mapping of human cortical development during childhood through early adulthood [Internet]. Proc Natl Acad Sci USA. 2004:8174–9. Available from: www.pnas.org/doi/10.1073/pnas.0402680101.

  6. Petanjek Z, Judaš M, Šimić G, Rašin MR, Uylings HBM, Rakic P, et al. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc Natl Acad Sci USA. 2011;108:13281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gabard-Durnam LJ, Flannery J, Goff B, Gee DG, Humphreys KL, Telzer E, et al. The development of human amygdala functional connectivity at rest from 4 to 23 years: a cross-sectional study. NeuroImage. 2014;95:193–207.

    Article  PubMed  Google Scholar 

  8. Parr AC, Calabro F, Larsen B, Tervo-Clemmens B, Elliot S, Foran W, et al. Dopamine-related striatal neurophysiology is associated with specialization of frontostriatal reward circuitry through adolescence. Prog Neurobiol. 2021;201:101997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sydnor VJ, Larsen B, Seidlitz J, Adebimpe A, Alexander-Bloch AF, Bassett DS, et al. Intrinsic activity development unfolds along a sensorimotor–association cortical axis in youth. Nat Neurosci. 2023;26:638–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hallquist MN, Geier CF, Luna B. Incentives facilitate developmental improvement in inhibitory control by modulating control-related networks. Neuroimage. 2018;172:369–80.

    Article  PubMed  Google Scholar 

  11. Ordaz SJ, Foran W, Velanova K, Luna B. Longitudinal growth curves of brain function underlying inhibitory control through adolescence. J Neurosci. 2013;33:18109–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Caballero A, Orozco A, Tseng KY. Developmental regulation of excitatory-inhibitory synaptic balance in the prefrontal cortex during adolescence. Semin Cell Dev Biol. 2021;118:60–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Larsen B, Cui Z, Adebimpe A, Pines A, Alexander-Bloch A, Bertolero M, et al. A developmental reduction of the excitation: inhibition ratio in association cortex during adolescence. Sci Adv. 2022;8:eabj8750.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Perica MI, Calabro FJ, Larsen B, Foran W, Yushmanov VE, Hetherington H, et al. Development of frontal GABA and glutamate supports excitation/inhibition balance from adolescence into adulthood. Prog Neurobiol. 2022;219:102370.

    Article  CAS  PubMed  Google Scholar 

  15. Anticevic A, Murray JD. Rebalancing altered computations: considering the role of neural excitation and inhibition balance across the psychiatric spectrum. Biol Psychiatry. 2017;81:816–7.

    Article  PubMed  Google Scholar 

  16. Howes OD, Shatalina E. Integrating the neurodevelopmental and dopamine hypotheses of schizophrenia and the role of cortical excitation-inhibition balance. Biol Psychiatry. 2022;92:501–13.

    Article  PubMed  Google Scholar 

  17. Lewis DA. Development of the prefrontal cortex during adolescence: insights into vulnerable neural circuits in schizophrenia. Neuropsychopharmacology. 1997;16:385–98.

    Article  CAS  PubMed  Google Scholar 

  18. Paus T, Keshavan M, Giedd JN. Why do many psychiatric disorders emerge during adolescence? Nat Rev Neurosci. 2008;9:947–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Selten M, van Bokhoven H, Nadif Kasri N. Inhibitory control of the excitatory/inhibitory balance in psychiatric disorders. F1000Res. 2018;7:23.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sohal VS, Rubenstein JLR. Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol Psychiatry. 2019;24:1248–57.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Vinogradov S, Chafee MV, Lee E, Morishita H. Psychosis spectrum illnesses as disorders of prefrontal critical period plasticity. Neuropsychopharmacol. 2023;48:168–85.

    Article  Google Scholar 

  22. Duman RS, Sanacora G, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102:75–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012;35:57–67.

    Article  CAS  PubMed  Google Scholar 

  24. Forbes NF, Carrick LA, McIntosh AM, Lawrie SM. Working memory in schizophrenia: a meta-analysis. Psychol Med. 2009;39:889–905.

    Article  CAS  PubMed  Google Scholar 

  25. Hensch TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 2005;6:877–88.

    Article  CAS  PubMed  Google Scholar 

  26. Levelt CN, Hübener M. Critical-period plasticity in the visual cortex. Annu Rev Neurosci. 2012;35:309–30.

    Article  CAS  PubMed  Google Scholar 

  27. Benes FM, Taylor JB, Cunningham MC. Convergence and plasticity of monoaminergic systems in the medial prefrontal cortex during the postnatal period: implications for the development of psychopathology. Cereb Cortex. 2000;10:1014–27.

    Article  CAS  PubMed  Google Scholar 

  28. Hoops D, Flores C. Making dopamine connections in adolescence. Trends Neurosci. 2017;40:709–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lambe EK, Krimer LS, Goldman-Rakic PS. Differential postnatal development of catecholamine and serotonin inputs to identified neurons in prefrontal cortex of rhesus monkey. J Neurosci. 2000;20:8780–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Leslie CA, Robertson MW, Cutler AJ, Bennett JP. Postnatal development of D1 dopamine receptors in the medial prefrontal cortex, striatum and nucleus accumbens of normal and neonatal 6-hydroxydopamine treated rats: a quantitative autoradiographic analysis. Brain Res Dev Brain Res. 1991;62:109–14.

    Article  CAS  PubMed  Google Scholar 

  31. Rosenberg DR, Lewis DA. Postnatal maturation of the dopaminergic innervation of monkey prefrontal and motor cortices: a tyrosine hydroxylase immunohistochemical analysis. J Comp Neurol. 1995;358:383–400.

    Article  CAS  PubMed  Google Scholar 

  32. Willing J, Cortes LR, Brodsky JM, Kim T, Juraska JM. Innervation of the medial prefrontal cortex by tyrosine hydroxylase immunoreactive fibers during adolescence in male and female rats. Dev Psychobiol. 2017;59:583–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kalsbeek A, Voorn P, Buijs RM, Pool CW, Uylings HBM. Development of the dopaminergic innervation in the prefrontal cortex of the rat. J Comp Neurol. 1988;269:58–72.

    Article  CAS  PubMed  Google Scholar 

  34. Manitt C, Eng C, Pokinko M, Ryan RT, Torres-Berrío A, Lopez JP, et al. dcc orchestrates the development of the prefrontal cortex during adolescence and is altered in psychiatric patients. Transl Psychiatry. 2013;3:e338–e338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Peters KZ, Naneix F. The role of dopamine and endocannabinoid systems in prefrontal cortex development: Adolescence as a critical period. Front Neural Circuits [Internet]. 2022 [cited 2022 Nov 16];[16]. Available from: https://www.frontiersin.org/articles/10.3389/fncir.2022.939235.

  36. Rosenberg DR, Lewis DA. Changes in the dopaminergic innervation of monkey prefrontal cortex during late postnatal development: a tyrosine hydroxylase immunohistochemical study. Biol Psychiatry. 1994;36:272–7.

    Article  CAS  PubMed  Google Scholar 

  37. Reynolds LM, Pokinko M, Torres-Berrío A, Cuesta S, Lambert LC, Del Cid Pellitero E, et al. DCC receptors drive prefrontal cortex maturation by determining dopamine axon targeting in adolescence. Biol Psychiatry. 2018;83:181–92.

    Article  CAS  PubMed  Google Scholar 

  38. O’Donnell P. Adolescent maturation of cortical dopamine. Neurotox Res. 2010;18:306–12.

    Article  PubMed  Google Scholar 

  39. Caballero A, Granberg R, Tseng KY. Mechanisms contributing to prefrontal cortex maturation during adolescence. Neurosci Biobehav Rev. 2016;70:4–12.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Fries P. A mechanism for cognitive dynamics: neuronal communication through neuronal coherence. Trends Cogn Sci. 2005;9:474–80.

    Article  PubMed  Google Scholar 

  41. Tseng KY, O’Donnell P. Dopamine–glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J Neurosci.2004;24:5131–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Flores-Barrera E, Thomases DR, Heng LJ, Cass DK, Caballero A, Tseng KY. Late adolescent expression of GluN2B transmission in the prefrontal cortex is input-specific and requires postsynaptic protein kinase A and D1 dopamine receptor signaling. Biol Psychiatry. 2014;75:508–16.

    Article  CAS  PubMed  Google Scholar 

  43. Tseng KY, O’Donnell P. Dopamine modulation of prefrontal cortical interneurons changes during adolescence. Cereb Cortex.2007;17:1235–40.

    Article  PubMed  Google Scholar 

  44. Reynolds LM, Flores C. Mesocorticolimbic dopamine pathways across adolescence: diversity in development. Front Neural Circuits. 2021;15:94.

    Article  Google Scholar 

  45. Puts NAJ, Edden RAE. In vivo magnetic resonance spectroscopy of GABA: A methodological review. Prog Nucl Magn Reson Spectrosc. 2012;60:29–41.

    Article  CAS  PubMed  Google Scholar 

  46. Ramadan S, Lin A, Stanwell P. Glutamate and glutamine: a review of in vivo MRS in the human brain. NMR Biomed. 2013;26:1630–46.

    Article  CAS  PubMed  Google Scholar 

  47. Bell T, Stokoe M, Harris AD. Macromolecule suppressed GABA levels show no relationship with age in a pediatric sample. Sci Rep. 2021;11:722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Deelchand DK, Marjańska M, Henry PG, Terpstra M. MEGA-PRESS of GABA+: influences of acquisition parameters. NMR Biomed. 2021;34:e4199.

    Article  CAS  PubMed  Google Scholar 

  49. Mikkelsen M, Barker PB, Bhattacharyya PK, Brix MK, Buur PF, Cecil KM, et al. Big GABA: edited MR spectroscopy at 24 research sites. NeuroImage. 2017;159:32–45.

    Article  CAS  PubMed  Google Scholar 

  50. Mikkelsen M, Rimbault DL, Barker PB, Bhattacharyya PK, Brix MK, Buur PF, et al. Big GABA II: water-referenced edited MR spectroscopy at 25 research sites. NeuroImage.2019;191:537–48.

    Article  CAS  PubMed  Google Scholar 

  51. Mullins PG, McGonigle DJ, O’Gorman RL, Puts NAJ, Vidyasagar R, Evans CJ, et al. Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA. NeuroImage. 2014;86:43–52.

    Article  CAS  PubMed  Google Scholar 

  52. Ghisleni C, Bollmann S, Poil SS, Brandeis D, Martin E, Michels L, et al. Subcortical glutamate mediates the reduction of short-range functional connectivity with age in a developmental cohort. J Neurosci. 2015;35:8433–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shimizu M, Suzuki Y, Yamada K, Ueki S, Watanabe M, Igarashi H, et al. Maturational decrease of glutamate in the human cerebral cortex from childhood to young adulthood: a 1 H-MR spectroscopy study. Pediatr Res. 2017;82:749–52.

    Article  CAS  PubMed  Google Scholar 

  54. Choi IY, Lee SP, Merkle H, Shen J. In vivo detection of gray and white matter differences in GABA concentration in the human brain. NeuroImage. 2006;33:85–93.

    Article  PubMed  Google Scholar 

  55. Pradhan S, Bonekamp S, Gillen JS, Rowland LM, Wijtenburg SA, Edden RAE, et al. Comparison of single voxel brain mrs at 3T and 7T using 32-channel head coils. Magn Reson Imaging. 2015;33:1013–8.

    Article  PubMed  PubMed Central  Google Scholar 

  56. McKeon SD, Perica MI, Parr AC, Calabro FJ, Foran W, Hetherington H, et al. Aperiodic EEG and 7T MRSI evidence for maturation of E/I balance supporting the development of working memory through adolescence. Dev Cogn Neurosci. 2024;66:101373.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Zhang S, Larsen B, Sydnor VJ, Zeng T, An L, Yan X, et al. In vivo whole-cortex marker of excitation-inhibition ratio indexes cortical maturation and cognitive ability in youth. Proc Natl Acad Sci USA. 2024;121:e2318641121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Torres-Vega A, Pliego-Rivero BF, Otero-Ojeda GA, Gómez-Oliván LM, Vieyra-Reyes P. Limbic system pathologies associated with deficiencies and excesses of the trace elements iron, zinc, copper, and selenium. Nutr Rev. 2012;70:679–92.

    Article  PubMed  Google Scholar 

  59. Ortega R, Cloetens P, Devès G, Carmona A, Bohic S. Iron storage within dopamine neurovesicles revealed by chemical nano-imaging. PLoS ONE [Internet]. 2007 Sep 26 [cited 2020 Feb 19];[2]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976597/.

  60. Lu LN, Qian ZM, Wu KC, Yung WH, Ke Y. Expression of iron transporters and pathological hallmarks of Parkinson’s and Alzheimer’s diseases in the brain of young, adult, and aged rats. Mol Neurobiol. 2017;54:5213–24.

    Article  CAS  PubMed  Google Scholar 

  61. Youdim MBH, Green AR. Iron deficiency and neurotransmitter synthesis and function. Proc Nutr Soc. 1978;37:173–9.

    Article  CAS  PubMed  Google Scholar 

  62. Youdim MBH. Monoamine oxidase inhibitors, and iron chelators in depressive illness and neurodegenerative diseases. J Neural Transm. 2018;125:1719–33.

    Article  CAS  PubMed  Google Scholar 

  63. Zucca FA, Segura-Aguilar J, Ferrari E, Muñoz P, Paris I, Sulzer D, et al. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. 2017;155:96–119.

    Article  CAS  PubMed  Google Scholar 

  64. Brass SD, Chen Nkuei, Mulkern RV, Bakshi R. Magnetic resonance imaging of iron deposition in neurological disorders. Top Magn Reson Imaging. 2006;17:31–40.

    Article  PubMed  Google Scholar 

  65. Connor JR, Menzies SL, Martin SMS, Mufson EJ. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J Neurosci Res. 1990;27:595–611.

    Article  CAS  PubMed  Google Scholar 

  66. Morris CM, Candy JM, Oakley AE, Bloxham CA, Edwardson JA. Histochemical distribution of non-haem iron in the human brain. Cell Tissues Organs.1992;144:235–57.

    Article  CAS  Google Scholar 

  67. Thomas LO, Boyko OB, Anthony DC, Burger PC. MR detection of brain iron. Am J Neuroradiol. 1993;14:1043–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Kilbourn MR. Radioligands for imaging vesicular monoamine transporters. In: Dierckx RAJO, Otte A, de Vries EFJ, van Waarde A, Luiten PGM, editors. PET and SPECT of neurobiological systems [Internet]. Berlin, Heidelberg: Springer; 2014 [cited 2020 Feb 19]. p. 765–790. Available from: https://doi.org/10.1007/978-3-642-42014-6_27.

  69. Larsen B, Olafsson V, Calabro F, Laymon C, Tervo-Clemmens B, Campbell E, et al. Maturation of the human striatal dopamine system revealed by PET and quantitative MRI. Nat Commun. 2020;11:1–10.

    Article  Google Scholar 

  70. Hallgren B, Sourander P. The effect of age on the non-haemin iron in the human brain. J Neurochem. 1958;3:41–51.

    Article  CAS  PubMed  Google Scholar 

  71. Aquino D, Bizzi A, Grisoli M, Garavaglia B, Bruzzone MG, Nardocci N, et al. Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects. Radiology. 2009;252:165–72.

    Article  PubMed  Google Scholar 

  72. Larsen B, Bourque J, Moore TM, Adebimpe A, Calkins ME, Elliott MA, et al. Longitudinal development of brain iron is linked to cognition in youth. J Neurosci 2020;40:1810–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Larsen B, Luna B. In vivo evidence of neurophysiological maturation of the human adolescent striatum. Dev Cogn Neurosci. 2015;12:74–85.

    Article  PubMed  Google Scholar 

  74. Peterson ET, Kwon D, Luna B, Larsen B, Prouty D, Bellis MDD, et al. Distribution of brain iron accrual in adolescence: evidence from cross-sectional and longitudinal analysis. Hum Brain Mapp. 2019;40:1480–95.

    Article  PubMed  Google Scholar 

  75. Wahlstrom D, Collins P, White T, Luciana M. Developmental changes in dopamine neurotransmission in adolescence: behavioral implications and issues in assessment. Brain Cogn. 2010;72:146–59.

    Article  PubMed  Google Scholar 

  76. Parr AC, Calabro F, Tervo-Clemmens B, Larsen B, Foran W, Luna B. Contributions of dopamine-related basal ganglia neurophysiology to the developmental effects of incentives on inhibitory control. Dev Cogn Neurosci. 2022;54:101100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hect JL, Daugherty AM, Hermez KM, Thomason ME. Developmental variation in regional brain iron and its relation to cognitive functions in childhood. Dev Cogn Neurosci. 2018;34:18–26.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Larsen B, Baller EB, Boucher AA, Calkins ME, Laney N, Moore TM, et al. Development of iron status measures during youth: associations with sex, neighborhood socioeconomic status, cognitive performance, and brain structure. Am J Clin Nutr. 2023;118:121–31.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Kwon H, Reiss AL, Menon V. Neural basis of protracted developmental changes in visuo-spatial working memory. Proc Natl Acad Sci USA. 2002;99:13336–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Scherf KS, Sweeney JA, Luna B. Brain basis of developmental change in visuospatial working memory. J Cog Neurosci. 2006;18:1045–58.

    Article  Google Scholar 

  81. Brown RW, Cheng YCN, Haacke EM, Thompson MR, Venkatesan R. Magnetic resonance imaging: physical principles and sequence design. New Jersey: John Wiley & Sons Inc; 2014. p. 976.

  82. Langkammer C, Krebs N, Goessler W, Scheurer E, Ebner F, Yen K, et al. Quantitative MR imaging of brain iron: a postmortem validation study. Radiology. 2010;257:455–62.

    Article  PubMed  Google Scholar 

  83. Schenck JF, Zimmerman EA. High-field magnetic resonance imaging of brain iron: birth of a biomarker? NMR Biomed. 2004;17:433–45.

    Article  CAS  PubMed  Google Scholar 

  84. McKeon SD, Calabro F, Thorpe RV, De La Fuente A, Foran W, Parr AC, et al. Age-related differences in transient gamma band activity during working memory maintenance through adolescence. NeuroImage. 2023;274:120112.

    Article  PubMed  Google Scholar 

  85. Price RB, Tervo-Clemmens BC, Panny B, Degutis M, Griffo A, Woody M. Biobehavioral correlates of an fMRI index of striatal tissue iron in depressed patients. Transl Psychiatry. 2021;11:1–8.

    Article  Google Scholar 

  86. Vo LTK, Walther DB, Kramer AF, Erickson KI, Boot WR, Voss MW, et al. Predicting individuals’ learning success from patterns of pre-learning mri activity. PLoS ONE. 2011;6:e16093.

  87. Siegel JS, Power JD, Dubis JW, Vogel AC, Church JA, Schlaggar BL, et al. Statistical improvements in functional magnetic resonance imaging analyses produced by censoring high-motion data points. Hum Brain Mapp. 2014;35:1981–96.

    Article  PubMed  Google Scholar 

  88. Jenkinson M, Beckmann CF, Behrens TE, Woolrich MW, Smith SM. FSL. NeuroImage. 2011;62:782–90.

    Article  PubMed  Google Scholar 

  89. Revelle WR psych: Procedures for personality and psychological research [Internet]. Evanston, Illinois: Northwestern University; 2022 [cited 2022 Apr 27]. Available from: https://CRAN.R-project.org/package=psych.

  90. Pan JW, Avdievich N, Hetherington HP. J-refocused coherence transfer spectroscopic imaging at 7 T in human brain. Magn Reson Med. 2010;64:1237–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hetherington HP, Avdievich NI, Kuznetsov AM, Pan JW. RF shimming for spectroscopic localization in the human brain at 7 T. Magn Reson Med. 2010;63:9–19.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30:672–9.

    Article  CAS  PubMed  Google Scholar 

  93. Provencher SW. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed. 2001;14:260–4.

    Article  CAS  PubMed  Google Scholar 

  94. Rackayova V, Cudalbu C, Pouwels PJW, Braissant O. Creatine in the central nervous system: from magnetic resonance spectroscopy to creatine deficiencies. Anal Biochem. 2017;529:144–57.

    Article  CAS  PubMed  Google Scholar 

  95. Saunders DE, Howe FA, Boogaart A, van den, Griffiths JR, Brown MM. Aging of the adult human brain: In vivo quantitation of metabolite content with proton magnetic resonance spectroscopy. J Magn Reson Imaging. 1999;9:711–6.

    Article  CAS  PubMed  Google Scholar 

  96. Andersson J, Jenkinson M, Smith S. Non-linear registration, aka spatial normalization. FMRIB technical report TR07JA2 [Internet]. 2007 [cited 2024 May 28]; Available from: https://fsl.fmrib.ox.ac.uk/fsl/oldwiki/FNIRT.html.

  97. Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res. 1996;29:162–73.

    Article  CAS  PubMed  Google Scholar 

  98. Hetherington HP, Kuzniecky RI, Vives K, Devinsky O, Pacia S, Luciano D, et al. A subcortical network of dysfunction in TLE measured by magnetic resonance spectroscopy. Neurology.2007;69:2256–65.

    Article  CAS  PubMed  Google Scholar 

  99. Montez DF, Calabro FJ, Luna B. The expression of established cognitive brain states stabilizes with working memory development. eLife Sci. 2017;6:e25606.

    Article  Google Scholar 

  100. Parr AC, Sydnor VJ, Calabro FJ, Luna B. Adolescent-to-adult gains in cognitive flexibility are adaptively supported by reward sensitivity, exploration, and neural variability. Curr Opin Behav Sci. 2024;58:101399.

    Article  PubMed  Google Scholar 

  101. Steel A, Mikkelsen M, Edden RAE, Robertson CE. Regional balance between glutamate+glutamine and GABA+ in the resting human brain. NeuroImage. 2020;220:117112.

    Article  CAS  PubMed  Google Scholar 

  102. Morris NM, Udry JR. Validation of a self-administered instrument to assess stage of adolescent development. J Youth Adolesc. 1980;9:271–80.

  103. Petersen AC, Crockett L, Richards M, Boxer A. A self-report measure of pubertal status: reliability, valdity, and initial norms. J Youth Adolesc. 1988;17:117–33.

    Article  CAS  PubMed  Google Scholar 

  104. Bond L, Clements J, Bertalli N, Evans-Whipp T, McMorris BJ, Patton GC, et al. A comparison of self-reported puberty using the Pubertal Development Scale and the Sexual Maturation Scale in a school-based epidemiologic survey. J Adolesc. 2006;29:709–20.

    Article  PubMed  Google Scholar 

  105. Ojha A, Parr AC, Foran W, Calabro FJ, Luna B. Puberty contributes to adolescent development of fronto-striatal functional connectivity supporting inhibitory control. Dev Cogn Neurosci. 2022;58:101183.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Ravindranath O, Calabro FJ, Foran W, Luna B. Pubertal development underlies optimization of inhibitory control through specialization of ventrolateral prefrontal cortex. Dev Cogn Neurosci. 2022;58:101162.

  107. Barendse MEA, Byrne ML, Flournoy JC, McNeilly EA, Guazzelli Williamson V, Barrett AMY, et al. Multimethod assessment of pubertal timing and associations with internalizing psychopathology in early adolescent girls. J Psychopathol Clin Sci. 2022;131:14–25.

    Article  PubMed  Google Scholar 

  108. Ellis BJ, Shirtcliff EA, Boyce WT, Deardorff J, Essex MJ. Quality of early family relationships and the timing and tempo of puberty: Effects depend on biological sensitivity to context. Dev Psychopathol. 2011;23:85–99.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Ladouceur CD, Kerestes R, Schlund MW, Shirtcliff EA, Lee Y, Dahl RE. Neural systems underlying reward cue processing in early adolescence: the role of puberty and pubertal hormones. Psychoneuroendocrinology. 2019;102:281–91.

    Article  CAS  PubMed  Google Scholar 

  110. Shirtcliff EA, Dahl RE, Pollak SD. Pubertal development: correspondence between hormonal and physical development. Child Dev. 2009;80:327–37.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Wood SN. Generalized additive models: an introduction with R. 1st ed. Boca Raton FL: Chapman & Hall/CRC; 2017. p. 341.

  112. Luna B, Garver KE, Urban TA, Lazar NA, Sweeney JA. Maturation of cognitive processes from late childhood to adulthood. Child Dev. 2004;75:1357–72.

    Article  PubMed  Google Scholar 

  113. Murty VP, Shah H, Montez D, Foran W, Calabro F, Luna B. Age-related trajectories of functional coupling between the VTA and nucleus accumbens depend on motivational state. J Neurosci. 2018;38:3508–17.

    Article  Google Scholar 

  114. Simmonds DJ, Hallquist MN, Luna B. Protracted development of executive and mnemonic brain systems underlying working memory in adolescence: a longitudinal fMRI study. NeuroImage. 2017;157:695–704.

    Article  PubMed  Google Scholar 

  115. Marra G, Wood SN. Practical variable selection for generalized additive models. Comput Stat Data Anal. 2011;55:2372–87.

    Article  Google Scholar 

  116. Wood SN. Stable and efficient multiple smoothing parameter estimation for generalized additive models. J Am Stat Assoc. 2004;99:673–86.

    Article  Google Scholar 

  117. Long JA. interactions: Comprehensive, User-Friendly Toolkit for Probing Interactions. [Internet]. Comprehensive R Archive Network (CRAN); 2019 [cited 2021 May 25]. Available from: https://CRAN.R-project.org/package=interactions.

  118. Suri D, Teixeira CM, Cagliostro MKC, Mahadevia D, Ansorge MS. Monoamine-sensitive developmental periods impacting adult emotional and cognitive behaviors. Neuropsychopharmacology. 2015;40:88–112.

    Article  PubMed  Google Scholar 

  119. Wang M, Barker PB, Cascella NG, Coughlin JM, Nestadt G, Nucifora FC, et al. Longitudinal changes in brain metabolites in healthy controls and patients with first episode psychosis: a 7-Tesla MRS study. Mol Psychiatry. 2023;28:2018–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Blüml S, Wisnowski JL, Nelson MD Jr, Paquette L, Gilles FH, et al. Metabolic maturation of the human brain from birth through adolescence: insights from in vivo magnetic resonance spectroscopy. Cereb Cortex. 2013;23:2944–55.

    Article  PubMed  Google Scholar 

  121. Gleich T, Lorenz RC, Pöhland L, Raufelder D, Deserno L, Beck A, et al. Frontal glutamate and reward processing in adolescence and adulthood. Brain Struct Funct. 2015;220:3087–99.

    Article  CAS  PubMed  Google Scholar 

  122. Harris LW, Lockstone HE, Khaitovich P, Weickert CS, Webster MJ, Bahn S. Gene expression in the prefrontal cortex during adolescence: implications for the onset of schizophrenia. BMC Med Genom. 2009;2:28.

    Article  Google Scholar 

  123. Henson MA, Roberts AC, Salimi K, Vadlamudi S, Hamer RM, Gilmore JH, et al. Developmental regulation of the NMDA receptor subunits, NR3A and NR1, in human prefrontal cortex. Cereb Cortex. 2008;18:2560–73.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Hoftman GD, Datta D, Lewis DA. Layer 3 excitatory and inhibitory circuitry in the prefrontal cortex: developmental trajectories and alterations in schizophrenia. Biol Psychiatry. 2017;81:862–73.

    Article  PubMed  Google Scholar 

  125. Han KS, Cooke SF, Xu W. Experience-dependent equilibration of AMPAR-mediated synaptic transmission during the critical period. Cell Rep. 2017;18:892–904.

    Article  CAS  PubMed  Google Scholar 

  126. Xu W, Löwel S, Schlüter OM. Silent synapse-based mechanisms of critical period plasticity. Front Cell Neurosci [Internet]. 2020 Jul 17 [cited 2024 May 28];[14]. Available from: https://www.frontiersin.org/articles/10.3389/fncel.2020.00213.

  127. Zhang Z, Jiao YY, Sun QQ. Developmental maturation of excitation and inhibition balance in principal neurons across four layers of somatosensory cortex. Neuroscience. 2011;174:10–25.

    Article  CAS  PubMed  Google Scholar 

  128. Porges EC, Jensen G, Foster B, Edden RA, Puts NA. The trajectory of cortical GABA across the lifespan, an individual participant data meta-analysis of edited MRS studies. eLife. 2021;10:e62575.

  129. Silveri MM, Sneider JT, Crowley DJ, Covell MJ, Acharya D, Rosso IM, et al. Frontal lobe γ-aminobutyric acid levels during adolescence: associations with impulsivity and response inhibition. Biol Psychiatry. 2013;74:296–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Caballero A, Flores-Barrera E, Cass DK, Tseng KY. Differential regulation of parvalbumin and calretinin interneurons in the prefrontal cortex during adolescence. Brain Struct Funct. 2014;219:395–406.

    Article  CAS  PubMed  Google Scholar 

  131. Erickson SL, Lewis DA. Postnatal development of parvalbumin- and GABA transporter-immunoreactive axon terminals in monkey prefrontal cortex. J Comp Neurol. 2002;448:186–202.

    Article  CAS  PubMed  Google Scholar 

  132. Fung SJ, Webster MJ, Sivagnanasundaram S, Duncan C, Elashoff M, Weickert CS. Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia. Am J Psychiatry 2010;167:1479–88.

    Article  PubMed  Google Scholar 

  133. Baker KD, Gray AR, Richardson R. The development of perineuronal nets around parvalbumin gabaergic neurons in the medial prefrontal cortex and basolateral amygdala of rats. Behav Neurosci. 2017;131:289–303.

    Article  CAS  PubMed  Google Scholar 

  134. Bourgeois JP, Goldman-Rakic PS, Rakic P. Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cereb Cortex. 1994;4:78–96.

    Article  CAS  PubMed  Google Scholar 

  135. Cruz DA, Eggan SM, Lewis DA. Postnatal development of pre- and postsynaptic GABA markers at chandelier cell connections with pyramidal neurons in monkey prefrontal cortex. J Comp Neurol. 2003;465:385–400.

    Article  PubMed  Google Scholar 

  136. Hashimoto T, Nguyen QL, Rotaru D, Keenan T, Arion D, Beneyto M, et al. Protracted developmental trajectories of GABAA receptor α1 and α2 subunit expression in primate prefrontal cortex. Biol Psychiatry. 2009;65:1015–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kilb W. Development of the GABAergic system from birth to adolescence. Neuroscientist. 2012;18:613–30.

    Article  PubMed  Google Scholar 

  138. Cools R, D’Esposito M. Inverted-u-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry. 2011;69:e113–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. D’Ardenne K, Eshel N, Luka J, Lenartowicz A, Nystrom LE, Cohen JD. Role of prefrontal cortex and the midbrain dopamine system in working memory updating. Proc Natl Acad Sci USA. 2012;109:19900–9.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Durstewitz D, Seamans JK. The computational role of dopamine D1 receptors in working memory. Neural Netw. 2002;15:561–72.

    Article  PubMed  Google Scholar 

  141. Floresco SB, Magyar O. Mesocortical dopamine modulation of executive functions: beyond working memory. Psychopharmacology. 2006;188:567–85.

    Article  CAS  PubMed  Google Scholar 

  142. Landau SM, Lal R, O’Neil JP, Baker S, Jagust WJ. Striatal dopamine and working memory. Cereb Cortex. 2009;19:445–54.

    Article  PubMed  Google Scholar 

  143. Connor JR, Menzies SL. Relationship of iron to oligodendrocytes and myelination. Glia. 1996;17:83–93.

    Article  CAS  PubMed  Google Scholar 

  144. Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR. Oligodendrocytes and myelination: the role of iron. Glia. 2009;57:467–78.

    Article  PubMed  Google Scholar 

  145. Surmeier DJ. Dopamine and working memory mechanisms in prefrontal cortex. J Physiol. 2007;581:885.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Zhang YQ, Lin WP, Huang LP, Zhao B, Zhang CC, Yin DM. Dopamine D2 receptor regulates cortical synaptic pruning in rodents. Nat Commun. 2021;12:6444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Nichols JA, Jakkamsetti VP, Salgado H, Dinh L, Kilgard MP, Atzori M. Environmental enrichment selectively increases glutamatergic responses in layer II/III of the auditory cortex of the rat. Neuroscience. 2007;145:832–40.

    Article  CAS  PubMed  Google Scholar 

  148. Gorelova N, Seamans JK, Yang CR. Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex. J Neurophysiol. 2002;88:3150–66.

    Article  CAS  PubMed  Google Scholar 

  149. Lew SE, Tseng KY. Dopamine modulation of GABAergic function enables network stability and input selectivity for sustaining working memory in a computational model of the prefrontal cortex. Neuropsychopharmacology. 2014;39:3067–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Enomoto T, Tse MT, Floresco SB. Reducing prefrontal gamma-aminobutyric acid activity induces cognitive, behavioral, and dopaminergic abnormalities that resemble schizophrenia. Biol Psychiatry. 2011;69:432–41.

    Article  CAS  PubMed  Google Scholar 

  151. Paine TA, Slipp LE, Carlezon WA. Schizophrenia-like attentional deficits following blockade of prefrontal cortex GABAA receptors. Neuropsychopharmacol. 2011;36:1703–13.

    Article  CAS  Google Scholar 

  152. Takado Y, Takuwa H, Sampei K, Urushihata T, Takahashi M, Shimojo M, et al. MRS-measured glutamate versus GABA reflects excitatory versus inhibitory neural activities in awake mice. J Cereb Blood Flow Metab. 2022;42:197–212.

    Article  CAS  PubMed  Google Scholar 

  153. Rae CD. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochem Res. 2014;39:1–36.

    Article  CAS  PubMed  Google Scholar 

  154. Porges EC, Jensen G, Foster B, Edden RA, Puts NA. The trajectory of cortical GABA across the lifespan, an individual participant data meta-analysis of edited MRS studies. eLife. 2021;10:e62575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Brenhouse HC, Sonntag KC, Andersen SL. Transient D1 dopamine receptor expression on prefrontal cortex projection neurons: relationship to enhanced motivational salience of drug cues in adolescence. J Neurosci. 2008 [cited 2020 Mar 6]; Available from: https://www.jneurosci.org/content/28/10/2375.short.

  156. Haber SN, Knutson B. The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology. 2010;35:4–26.

    Article  PubMed  Google Scholar 

  157. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357–81.

    Article  CAS  PubMed  Google Scholar 

  158. Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends Neurosci. 1989;12:366–75.

    Article  CAS  PubMed  Google Scholar 

  159. Obeso JA, Lanciego JL. Past, present, and future of the pathophysiological model of the basal ganglia. Front Neuroanat [Internet]. 2011 Jul 12 [cited 2024 May 28];5. Available from: https://www.frontiersin.org/articles/10.3389/fnana.2011.00039.

  160. Stephenson-Jones M, Ericsson J, Robertson B, Grillner S. Evolution of the basal ganglia: dual-output pathways conserved throughout vertebrate phylogeny. J Comp Neurol. 2012;520:2957–73.

    Article  PubMed  Google Scholar 

  161. Utter AA, Basso MA. The basal ganglia: an overview of circuits and function. Neurosci Biobehav Rev. 2008;32:333–42.

    Article  PubMed  Google Scholar 

  162. Griffith HR, Okonkwo OC, O’Brien T, den Hollander JA. Reduced brain glutamate in patients with Parkinson’s disease. NMR Biomed. 2008;21:381–7.

    Article  CAS  PubMed  Google Scholar 

  163. Barbeito L, Chéramy A, Godeheu G, Desce JM, Glowinski J. Glutamate receptors of a quisqualate-kainate subtype are involved in the presynaptic regulation of dopamine release in the cat caudate nucleus in vivo. Eur J Neurosci. 1990;2:304–11.

    Article  PubMed  Google Scholar 

  164. Beckstead RM. Convergent prefrontal and nigral projections to the striatum of the rat. Neurosci Lett. 1979;12:59–64.

    Article  CAS  PubMed  Google Scholar 

  165. Cai NS, Kiss B, Erdö SL. Heterogeneity of N-Methyl-D-aspartate receptors regulating the release of dopamine and acetylcholine from striatal slices. J Neurochem. 1991;57:2148–51.

    Article  CAS  PubMed  Google Scholar 

  166. Clow DW, Jhamandas K. Characterization of L-glutamate action on the release of endogenous dopamine from the rat caudate-putamen. J Pharm Exp Ther. 1989;248:722–8.

    Article  CAS  Google Scholar 

  167. Dalsass M, Kiser S, Mèndershausen M, German DC. Medial prefrontal cortical projections to the region of the dorsal periventricular catecholamine system. Neuroscience. 1981;6:657–65.

    Article  CAS  PubMed  Google Scholar 

  168. Fonnum F, Storm-Mathisen J, Divac I. Biochemical evidence for glutamate as neurotransmitter in corticostriatal and corticothalamic fibres in rat brain. Neuroscience. 1981;6:863–73.

    Article  CAS  PubMed  Google Scholar 

  169. Imperato A, Honore´ T, Jensen LH. Dopamine release in the nucleus caudatus and in the nucleus accumbens is under glutamatergic control through non-NMDA receptors: a study in freely-moving rats. Brain Res. 1990;530:223–8.

    Article  CAS  PubMed  Google Scholar 

  170. Karreman M, Moghaddam B. The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem. 1996;66:589–98.

    Article  CAS  PubMed  Google Scholar 

  171. Krebs MO, Trovero F, Desban M, Gauchy C, Glowinski J, Kemel ML. Distinct presynaptic regulation of dopamine release through NMDA receptors in striosome- and matrix-enriched areas of the rat striatum. J Neurosci 1991;11:1256–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Leviel V, Gobert A, Guibert B. The glutamate-mediated release of dopamine in the rat striatum: further characterization of the dual excitatory-inhibitory function. Neuroscience. 1990;39:305–12.

    Article  CAS  PubMed  Google Scholar 

  173. Moghaddam B, Roth RH, Bunney BS. Characterization of dopamine release in the rat medial prefrontal cortex as assessed by in vivo microdialysis: comparison to the striatum. Neuroscience.1990;36:669–76.

    Article  CAS  PubMed  Google Scholar 

  174. Roberts PJ, Anderson SD. Stimulatory effect of l-glutamate and related amino acids on [3H] dopamine release from rat striatum: an in vitro model for glutamate actions. J Neurochem. 1979;32:1539–45.

    Article  CAS  PubMed  Google Scholar 

  175. Sesack SR, Deutch AY, Roth RH, Bunney BS. Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J Comp Neurol. 1989;290:213–42.

    Article  CAS  PubMed  Google Scholar 

  176. Youngren KD, Moghaddam B, Bunney BS, Roth RH. Preferential activation of dopamine overflow in prefrontal cortex produced by chronic clozapine treatment. Neurosci Lett. 1994;165:41–4.

    Article  CAS  PubMed  Google Scholar 

  177. Youngren KD, Inglis FM, Pivirotto PJ, Jedema HP, Bradberry CW, Goldman-Rakic PS, et al. Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus. Neuropsychopharmacol. 1999;20:403–12.

    Article  CAS  Google Scholar 

  178. Murase S, Grenhoff J, Chouvet G, Gonon FG, Svensson TH. Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo. Neurosci Lett. 1993;157:53–6.

    Article  CAS  PubMed  Google Scholar 

  179. Sesack SR, Pickel VM. Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol. 1992;320:145–60.

    Article  CAS  PubMed  Google Scholar 

  180. Descarries L, Bérubé-Carrière N, Riad M, Bo GD, Mendez JA, Trudeau LÉ. Glutamate in dopamine neurons: synaptic versus diffuse transmission. Brain Res Rev. 2008;58:290–302.

    Article  CAS  PubMed  Google Scholar 

  181. Rayport S. Glutamate is a cotransmitter in ventral midbrain dopamine neurons. Parkinsonism Relat Disord. 2001;7:261–4.

    Article  CAS  PubMed  Google Scholar 

  182. Sulzer D, Joyce MP, Lin L, Geldwert D, Haber SN, Hattori T, et al. Dopamine neurons make glutamatergic synapses in vitro. J Neurosci. 1998;18:4588–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Cline H, Haas K. The regulation of dendritic arbor development and plasticity by glutamatergic synaptic input: a review of the synaptotrophic hypothesis. J Physiol. 2008;586:1509–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Ruediger T, Bolz J. Neurotransmitters and the development of neuronal circuits. In: Bagnard D, editor. Axon growth and guidance [Internet]. New York, NY: Springer; 2007 [cited 2024 May 28]. p. 104–114. Available from: https://doi.org/10.1007/978-0-387-76715-4_8.

  185. Sabo SL, Gomes RA, McAllister AK. Formation of presynaptic terminals at predefined sites along axons. J Neurosci 2006;26:10813–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Bérubé-Carrière N, Riad M, Dal Bo G, Lévesque D, Trudeau LÉ, Descarries L. The dual dopamine-glutamate phenotype of growing mesencephalic neurons regresses in mature rat brain. J Comp Neurol. 2009;517:873–91.

    Article  PubMed  Google Scholar 

  187. Larsen B, Sydnor VJ, Keller AS, Yeo BTT, Satterthwaite TD. A critical period plasticity framework for the sensorimotor–association axis of cortical neurodevelopment. Trends Neurosci .2023;46:847–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Tooley UA, Bassett DS, Mackey AP. Environmental influences on the pace of brain development. Nat Rev Neurosci. 2021;22:372–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Baroncelli L, Braschi C, Spolidoro M, Begenisic T, Sale A, Maffei L. Nurturing brain plasticity: impact of environmental enrichment. Cell Death Differ. 2010;17:1092–103.

    Article  CAS  PubMed  Google Scholar 

  190. Huang L, Jin J, Chen K, You S, Zhang H, Sideris A, et al. BDNF produced by cerebral microglia promotes cortical plasticity and pain hypersensitivity after peripheral nerve injury. PLoS Biol. 2021;19:e3001337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Sale A, Maya Vetencourt JF, Medini P, Cenni MC, Baroncelli L, De Pasquale R, et al. Environmental enrichment in adulthood promotes amblyopia recovery through a reduction of intracortical inhibition. Nat Neurosci. 2007;10:679–81.

    Article  CAS  PubMed  Google Scholar 

  192. Greifzu F, Pielecka-Fortuna J, Kalogeraki E, Krempler K, Favaro PD, Schlüter OM, et al. Environmental enrichment extends ocular dominance plasticity into adulthood and protects from stroke-induced impairments of plasticity. Proc Natl Acad Sci USA. 2014;111:1150–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Favuzzi E, Marques-Smith A, Deogracias R, Winterflood CM, Sánchez-Aguilera A, Mantoan L, et al. Activity-dependent gating of parvalbumin interneuron function by the perineuronal net protein brevican. Neuron.2017;95:639–55.e10.

    Article  CAS  PubMed  Google Scholar 

  194. Han K, Lee M, Lim HK, Jang MW, Kwon J, Lee CJ, et al. Excitation-inhibition imbalance leads to alteration of neuronal coherence and neurovascular coupling under acute stress. J Neurosci. 2020;40:9148–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Catale C, Martini A, Piscitelli RM, Senzasono B, Iacono LL, Mercuri NB, et al. Early-life social stress induces permanent alterations in plasticity and perineuronal nets in the mouse anterior cingulate cortex. Eur J Neurosci. 2022;56:5763–83.

    Article  CAS  PubMed  Google Scholar 

  196. Perica MI, Luna B. Impact of stress on excitatory and inhibitory markers of adolescent cognitive critical period plasticity. Neurosci Biobehav Rev. 2023;153:105378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment. World Psychiatry. 2020;19:15–33.

    Article  PubMed  PubMed Central  Google Scholar 

  198. Howes OD, Murray RM. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet. 2014;383:1677–87.

    Article  PubMed  Google Scholar 

  199. Sonnenschein SF, Parr AC, Larsen B, Calabro FJ, Foran W, Eack SM, et al. Subcortical brain iron deposition in individuals with schizophrenia. J Psychiatr Res. 2022;151:272–8.

    Article  PubMed  Google Scholar 

  200. Wang AM, Pradhan S, Coughlin JM, Trivedi A, DuBois SL, Crawford JL, et al. Assessing brain metabolism with 7-T proton magnetic resonance spectroscopy in patients with first-episode psychosis. JAMA Psychiatry. 2019;76:314–23.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Reid MA, Salibi N, White DM, Gawne TJ, Denney TS, Lahti AC. 7T proton magnetic resonance spectroscopy of the anterior cingulate cortex in first-episode schizophrenia. Schizophr Bull. 2019;45:180–9.

    Article  PubMed  Google Scholar 

  202. Kumar J, Liddle EB, Fernandes CC, Palaniyappan L, Hall EL, Robson SE, et al. Glutathione and glutamate in schizophrenia: a 7T MRS study. Mol Psychiatry. 2020;25:873–82.

    Article  CAS  PubMed  Google Scholar 

  203. Brandt AS, Unschuld PG, Pradhan S, Lim IAL, Churchill G, Harris AD, et al. Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A 1H MRS Study at 7 Tesla. Schizophr Res. 2016;172:101–5.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Thakkar KN, Rösler L, Wijnen JP, Boer VO, Klomp DWJ, Cahn W, et al. 7T proton magnetic resonance spectroscopy of gamma-aminobutyric acid, glutamate, and glutamine reveals altered concentrations in patients with schizophrenia and healthy siblings. Biol Psychiatry. 2017;81:525–35.

    Article  CAS  PubMed  Google Scholar 

  205. Marsman A, Mandl RCW, Klomp DWJ, Bohlken MM, Boer VO, Andreychenko A, et al. GABA and glutamate in schizophrenia: a 7T 1H-MRS study. NeuroImage Clin 2014;6:398–407.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the participants, the research assistants, and the University of Pittsburgh Clinical and Translational Science Institute (CTSI) for help in recruiting participants, and Dr. Valerie J Sydnor & Amar Ojha for comments on an earlier draft.

Funding

This work was supported by Grant Number 5RO1MH080243-07 (for ACP, FJC, and BL) from the National Library of Medicine, National Institutes of Health, the Brain and Behavior Research Foundation (BBRF; to ACP) and the Staunton Farm Foundation.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    Ashley C. Parr, Maria I. Perica, Finnegan J. Calabro, Will Foran & Beatriz Luna

  2. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Finnegan J. Calabro

  3. Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA

    Chan Hong Moon

  4. Resonance Research Incorporated, Billerica, MA, USA

    Hoby Hetherington

Authors
  1. Ashley C. Parr
    View author publications

    Search author on:PubMed Google Scholar

  2. Maria I. Perica
    View author publications

    Search author on:PubMed Google Scholar

  3. Finnegan J. Calabro
    View author publications

    Search author on:PubMed Google Scholar

  4. Will Foran
    View author publications

    Search author on:PubMed Google Scholar

  5. Chan Hong Moon
    View author publications

    Search author on:PubMed Google Scholar

  6. Hoby Hetherington
    View author publications

    Search author on:PubMed Google Scholar

  7. Beatriz Luna
    View author publications

    Search author on:PubMed Google Scholar

Contributions

ACP, BL, and FJC designed the study; HH and CHM collected the data; ACP, FC, MIP, and WF analyzed the data; ACP drafted the manuscript with input from FJC, MIP, and BL.

Corresponding author

Correspondence to Ashley C. Parr.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parr, A.C., Perica, M.I., Calabro, F.J. et al. Adolescent maturation of dorsolateral prefrontal cortex glutamate:GABA and cognitive function is supported by dopamine-related neurobiology. Mol Psychiatry 30, 2558–2572 (2025). https://doi.org/10.1038/s41380-024-02860-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41380-024-02860-7

This article is cited by

Search

Advanced search

Quick links