Abstract
Working memory requires the activity of parvalbumin (PV) interneurons in the dorsolateral prefrontal cortex (DLPFC). Impaired working memory and lower PV expression in the DLPFC are reported in schizophrenia and to a lesser degree in mood disorders. We previously proposed that activity-dependent PV expression is lower in schizophrenia due to a shift in the splicing of erb-b2 receptor tyrosine kinase 4 (ErbB4) transcripts from major to inactive minor variants that reduces excitatory drive to PV interneurons. Here, we tested the hypothesis that the degree of major-to-minor shift in ErbB4 splicing predicts the level of PV expression across schizophrenia and mood disorders. Levels of ErbB4 splice variants and PV mRNA were quantified by PCR in the DLPFC from 40 matched tetrads (N = 160 subjects) of schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), and unaffected comparison subjects. Relative to unaffected comparison subjects, the magnitude of increases in minor variant levels and decreases in major variant levels was greatest in schizophrenia, intermediate in BD, and least in MDD. The same rank order was present for the magnitude of increases in the composite splicing score, which reflects the degree of major-to-minor shift across all ErbB4 splice loci, and for the magnitude of deficient PV expression. Finally, the composite splicing score negatively predicted PV expression across all subject groups. Together, these findings demonstrate a shared relationship between ErbB4 splicing and PV expression and suggest that scaling of the major-to-minor shift in ErbB4 splicing may influence the severity of deficient PV interneuron activity across diagnoses.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Gold JM, Carpenter C, Randolph C, Goldberg TE, Weinberger DR. Auditory working memory and Wisconsin card sorting test performance in schizophrenia. Arch Gen Psychiatry. 1997;54:159–65.
Lee J, Park S. Working memory impairments in schizophrenia: a meta-analysis. J Abnorm Psychol. 2005;114:599–611.
Park S, Holzman PS. Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry. 1992;49:975–82.
Bora E, Yucel M, Pantelis C. Cognitive endophenotypes of bipolar disorder: a meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. J Affect Disord. 2009;113:1–20.
Martinez-Aran A, Vieta E, Reinares M, Colom F, Torrent C, Sanchez-Moreno J, et al. Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am J Psychiatry. 2004;161:262–70.
Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095–105.
Porter RJ, Gallagher P, Thompson JM, Young AH. Neurocognitive impairment in drug-free patients with major depressive disorder. Br J Psychiatry. 2003;182:214–20.
Evans VC, Iverson GL, Yatham LN, Lam RW. The relationship between neurocognitive and psychosocial functioning in major depressive disorder: a systematic review. J Clin Psychiatry. 2014;75:1359–70.
Kahn RS, Keefe RS. Schizophrenia is a cognitive illness: time for a change in focus. JAMA Psychiatry. 2013;70:1107–12.
Bora E, Yucel M, Pantelis C. Cognitive impairment in schizophrenia and affective psychoses: implications for DSM-V criteria and beyond. Schizophr Bull. 2010;36:36–42.
Goldberg TE, Gold JM, Greenberg R, Griffin S, Schulz SC, Pickar D, et al. Contrasts between patients with affective disorders and patients with schizophrenia on a neuropsychological test battery. Am J Psychiatry. 1993;150:1355–62.
Reichenberg A, Harvey PD, Bowie CR, Mojtabai R, Rabinowitz J, Heaton RK, et al. Neuropsychological function and dysfunction in schizophrenia and psychotic affective disorders. Schizophr Bull. 2009;35:1022–9.
Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012;35:57–67.
Patz S, Grabert J, Gorba T, Wirth MJ, Wahle P. Parvalbumin expression in visual cortical interneurons depends on neuronal activity and TrkB ligands during an Early period of postnatal development. Cereb Cortex. 2004;14:342–51.
Philpot BD, Lim JH, Brunjes PC. Activity-dependent regulation of calcium-binding proteins in the developing rat olfactory bulb. J Comp Neurol. 1997;387:12–26.
Beasley CL, Zhang ZJ, Patten I, Reynolds GP. Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Biol Psychiatry. 2002;52:708–15.
Chung DW, Fish KN, Lewis DA. Pathological basis for deficient excitatory drive to cortical parvalbumin interneurons in schizophrenia. Am J Psychiatry. 2016;173:1131–9.
Chung DW, Volk DW, Arion D, Zhang Y, Sampson AR, Lewis DA. Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression. Am J Psychiatry. 2016;173:60–8.
Enwright JF, Sanapala S, Foglio A, Berry R, Fish KN, Lewis DA. Reduced labeling of parvalbumin neurons and perineuronal nets in the dorsolateral prefrontal cortex of subjects with schizophrenia. Neuropsychopharmacology. 2016;41:2206–14.
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.
Glausier JR, Fish KN, Lewis DA. Altered parvalbumin basket cell inputs in the dorsolateral prefrontal cortex of schizophrenia subjects. Mol Psychiatry. 2014;19:30–6.
Hashimoto T, Volk DW, Eggan SM, Mirnics K, Pierri JN, Sun Z, et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci. 2003;23:6315–26.
Mellios N, Huang HS, Baker SP, Galdzicka M, Ginns E, Akbarian S. Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia. Biol Psychiatry. 2009;65:1006–14.
Volk DW, Matsubara T, Li S, Sengupta EJ, Georgiev D, Minabe Y, et al. Deficits in transcriptional regulators of cortical parvalbumin neurons in schizophrenia. Am J Psychiatry. 2012;169:1082–91.
Rajkowska G, O’Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ. GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology. 2007;32:471–82.
Sakai T, Oshima A, Nozaki Y, Ida I, Haga C, Akiyama H, et al. Changes in density of calcium-binding-protein-immunoreactive GABAergic neurons in prefrontal cortex in schizophrenia and bipolar disorder. Neuropathology. 2008;28:143–50.
Sibille E, Morris HM, Kota RS, Lewis DA. GABA-related transcripts in the dorsolateral prefrontal cortex in mood disorders. Int J Neuropsychopharmacol. 2011;14:721–34.
Mei L, Nave KA. Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron. 2014;83:27–49.
Bublil EM, Yarden Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr Opin Cell Biol. 2007;19:124–34.
Neddens J, Fish KN, Tricoire L, Vullhorst D, Shamir A, Chung W, et al. Conserved interneuron-specific ErbB4 expression in frontal cortex of rodents, monkeys, and humans: implications for schizophrenia. Biol Psychiatry. 2011;70:636–45.
Vullhorst D, Neddens J, Karavanova I, Tricoire L, Petralia RS, McBain CJ, et al. Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. J Neurosci. 2009;29:12255–64.
Del Pino I, Garcia-Frigola C, Dehorter N, Brotons-Mas JR, Alvarez-Salvado E, Martinez de Lagran M, et al. Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes. Neuron. 2013;79:1152–68.
Ting AK, Chen Y, Wen L, Yin DM, Shen C, Tao Y, et al. Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons. J Neurosci. 2011;31:15–25.
Veikkolainen V, Vaparanta K, Halkilahti K, Iljin K, Sundvall M, Elenius K. Function of ERBB4 is determined by alternative splicing. Cell Cycle. 2011;10:2647–57.
Erben L, He MX, Laeremans A, Park E, Buonanno A. A novel ultrasensitive in situ hybridization approach to detect short sequences and splice variants with cellular resolution. Mol Neurobiol. 2017;55:6169–81.
Chung DW, Wills ZP, Fish KN, Lewis DA. Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex. Proc Natl Acad Sci USA. 2017;114:E629–37.
Joshi D, Fullerton JM, Weickert CS. Elevated ErbB4 mRNA is related to interneuron deficit in prefrontal cortex in schizophrenia. J Psychiatr Res. 2014;53:125–32.
Law AJ, Kleinman JE, Weinberger DR, Weickert CS. Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. Hum Mol Genet. 2007;16:129–41.
Silberberg G, Darvasi A, Pinkas-Kramarski R, Navon R. The involvement of ErbB4 with schizophrenia: association and expression studies. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:142–8.
Hashimoto T, Bazmi HH, Mirnics K, Wu Q, Sampson AR, Lewis DA. Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. Am J Psychiatry. 2008;165:479–89.
Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Erlbaum Associates; 1988. p. 567.
Nakagawa S, Cuthill IC. Effect size, confidence interval and statistical significance: a practical guide for biologists. Biol Rev Camb Philos Soc. 2007;82:591–605.
Hoftman GD, Dienel SJ, Bazmi HH, Zhang Y, Chen K, Lewis DA. Altered gradients of glutamate and gamma-aminobutyric acid transcripts in the cortical visuospatial working memory network in schizophrenia. Biol Psychiatry. 2018;83:670–9.
Chang MC, Park JM, Pelkey KA, Grabenstatter HL, Xu D, Linden DJ, et al. Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons. Nat Neurosci. 2010;13:1090–7.
Kimoto S, Zaki MM, Bazmi HH, Lewis DA. Altered markers of cortical gamma-aminobutyric acid neuronal activity in schizophrenia: role of the NARP gene. JAMA Psychiatry. 2015;72:747–56.
Pelkey KA, Barksdale E, Craig MT, Yuan X, Sukumaran M, Vargish GA, et al. Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons. Neuron. 2015;85:1257–72.
Gonzalez-Burgos G, Cho RY, Lewis DA. Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia. Biol Psychiatry. 2015;77:1031–40.
Acknowledgements
We thank Kelly Rogers (University of Pittsburgh) and Mary Brady (University of Pittsburgh) for their technical assistance. Tissue samples from ten subjects used in this study were obtained from the NIH NeuroBioBank repository at the University of Pittsburgh. This work was supported by NIH grants MH043784 (to DAL) and MH103204 (to DAL). DAL currently receives investigator-initiated research support from Pfizer and serves as a consultant in the areas of target identification and validation and new compound development to Merck.
Author information
Authors and Affiliations
Corresponding author
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.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Chung, D.W., Chung, Y., Bazmi, H.H. et al. Altered ErbB4 splicing and cortical parvalbumin interneuron dysfunction in schizophrenia and mood disorders. Neuropsychopharmacol 43, 2478–2486 (2018). https://doi.org/10.1038/s41386-018-0169-7
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41386-018-0169-7
This article is cited by
-
A spatial long-read approach at near-single-cell resolution reveals developmental regulation of splicing and polyadenylation sites in distinct cortical layers and cell types
Nature Communications (2025)
-
Mean-field analysis of synaptic alterations underlying deficient cortical gamma oscillations in schizophrenia
Journal of Computational Neuroscience (2025)
-
Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia
Molecular Psychiatry (2024)
-
Postmortem evidence of decreased brain pH in major depressive disorder: a systematic review and meta-analysis
Translational Psychiatry (2024)
-
Altered excitatory and inhibitory ionotropic receptor subunit expression in the cortical visuospatial working memory network in schizophrenia
Neuropsychopharmacology (2024)
