Abstract
Astrocytes are implicated in information processing, signal transmission, and regulation of synaptic plasticity. Aquaporin-4 (AQP4) is the major water channel in adult brain and is primarily expressed in astrocytes. A growing body of evidence indicates that AQP4 is a potential molecular target for the regulation of astrocytic function. However, little is known about the role of AQP4 in synaptic plasticity in the amygdala. Therefore, we evaluated long-term potentiation (LTP) in the lateral amygdala (LA) and associative fear memory of AQP4 knockout (KO) and wild-type mice. We found that AQP4 deficiency impaired LTP in the thalamo-LA pathway and associative fear memory. Furthermore, AQP4 deficiency significantly downregulated glutamate transporter-1 (GLT-1) expression and selectively increased NMDA receptor (NMDAR)-mediated EPSCs in the LA. However, low concentration of NMDAR antagonist reversed the impairment of LTP in KO mice. Upregulating GLT-1 expression by chronic treatment with ceftriaxone also reversed the impairment of LTP and fear memory in KO mice. These findings imply a role for AQP4 in synaptic plasticity and associative fear memory in the amygdala by regulating GLT-1 expression.
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References
Abel T, Lattal KM (2001). Molecular mechanisms of memory acquisition, consolidation and retrieval. Curr Opin Neurobiol 11: 180–187.
Amara SG, Fontana AC (2002). Excitatory amino acid transporters: keeping up with glutamate. Neurochem Int 41: 313–318.
Amiry-Moghaddam M, Ottersen OP (2003). The molecular basis of water transport in the brain. Nat Rev Neurosci 4: 991–1001.
Bao F, Chen M, Zhang Y, Zhao Z (2010). Hypoalgesia in mice lacking aquaporin-4 water channels. Brain Res Bull 83: 298–303.
Barad M, Gean PW, Lutz B (2006). The role of the amygdala in the extinction of conditioned fear. Biol Psychiatry 60: 322–328.
Binder DK, Papadopoulos MC, Haggie PM, Verkman AS (2004). In vivo measurement of brain extracellular space diffusion by cortical surface photobleaching. J Neurosci 24: 8049–8056.
Binder DK, Yao X, Zador Z, Sick TJ, Verkman AS, Manley GT (2006). Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia 53: 631–636.
Chi Y, Fan Y, He L, Liu W, Wen X, Zhou S et al (2011). Novel role of aquaporin-4 in CD4+ CD25+ T regulatory cell development and severity of Parkinson's disease. Aging Cell 10: 368–382.
Citri A, Malenka RC (2008). Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 33: 18–41.
Clements JD (1996). Transmitter timecourse in the synaptic cleft: its role in central synaptic function. Trends Neurosci 19: 163–171.
Danbolt NC (2001). Glutamate uptake. Prog Neurobiol 65: 1–105.
Davis M (1992). The role of the amygdala in fear and anxiety. Annu Rev Neurosci 15: 353–375.
Ding JY, Kreipke CW, Speirs SL, Schafer P, Schafer S, Rafols JA (2009). Hypoxia-inducible factor-1alpha signaling in aquaporin upregulation after traumatic brain injury. Neurosci Lett 453: 68–72.
Fan Y, Kong H, Shi X, Sun X, Ding J, Wu J et al (2008). Hypersensitivity of aquaporin 4-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine and astrocytic modulation. Neurobiol Aging 29: 1226–1236.
Fan Y, Zhang J, Sun XL, Gao L, Zeng XN, Ding JH et al (2005). Sex- and region-specific alterations of basal amino acid and monoamine metabolism in the brain of aquaporin-4 knockout mice. J Neurosci Res 82: 458–464.
Friedman B, Schachtrup C, Tsai PS, Shih AY, Akassoglou K, Kleinfeld D et al (2009). Acute vascular disruption and aquaporin 4 loss after stroke. Stroke 40: 2182–2190.
Gladding CM, Raymond LA (2011). Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function. Mol Cell Neurosci 48: 308–320.
Hardingham GE, Bading H (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11: 682–696.
Haydon PG, Blendy J, Moss SJ, Rob Jackson F (2009). Astrocytic control of synaptic transmission and plasticity: a target for drugs of abuse? Neuropharmacology 56 (Suppl 1): 83–90.
Henneberger C, Papouin T, Oliet SH, Rusakov DA (2010). Long-term potentiation depends on release of D-serine from astrocytes. Nature 463: 232–236.
Jung SY, Kim J, Kwon OB, Jung JH, An K, Jeong AY et al (2010). Input-specific synaptic plasticity in the amygdala is regulated by neuroligin-1 via postsynaptic NMDA receptors. Proc Natl Acad Sci USA 107: 4710–4715.
Katagiri H, Tanaka K, Manabe T (2001). Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction. Eur J Neurosci 14: 547–553.
Kettenmann H, Ransom BR (2005). Neuroglia, 2nd edn. Oxford University Press: New York, p. xix, 601pp.
Kim JJ, Jung MW (2006). Neural circuits and mechanisms involved in Pavlovian fear conditioning: a critical review. Neurosci Biobehav Rev 30: 188–202.
Knackstedt LA, Melendez RI, Kalivas PW (2010). Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry 67: 81–84.
Kong H, Sha LL, Fan Y, Xiao M, Ding JH, Wu J et al (2009). Requirement of AQP4 for antidepressive efficiency of fluoxetine: implication in adult hippocampal neurogenesis. Neuropsychopharmacology 34: 1263–1276.
LeDoux JE (2000). Emotion circuits in the brain. Annu Rev Neurosci 23: 155–184.
Lee EJ, Son GH, Chung S, Lee S, Kim J, Choi S et al (2011). Impairment of fear memory consolidation in maternally stressed male mouse offspring: evidence for nongenomic glucocorticoid action on the amygdala. J Neurosci 31: 7131–7140.
Li J, Verkman AS (2001). Impaired hearing in mice lacking aquaporin-4 water channels. J Biol Chem 276: 31233–31237.
Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ (2011). Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci 31: 6627–6638.
Ma T, Yang B, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS (1997). Generation and phenotype of a transgenic knockout mouse lacking the mercurial-insensitive water channel aquaporin-4. J Clin Invest 100: 957–962.
Makkar SR, Zhang SQ, Cranney J (2010). Behavioral and neural analysis of GABA in the acquisition, consolidation, reconsolidation, and extinction of fear memory. Neuropsychopharmacology 35: 1625–1652.
Malenka RC (2003). The long-term potential of LTP. Nat Rev Neurosci 4: 923–926.
Malenka RC, Nicoll RA (1999). Long-term potentiation—a decade of progress? Science 285: 1870–1874.
Mayer ML, Westbrook GL (1987). The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 28: 197–276.
Miller BR, Dorner JL, Shou M, Sari Y, Barton SJ, Sengelaub DR et al (2008). Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington's disease phenotype in the R6/2 mouse. Neuroscience 153: 329–337.
Mothet JP, Rouaud E, Sinet PM, Potier B, Jouvenceau A, Dutar P et al (2006). A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory. Aging Cell 5: 267–274.
Nagelhus EA, Mathiisen TM, Ottersen OP (2004). Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1. Neuroscience 129: 905–913.
Neves G, Cooke SF, Bliss TV (2008). Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci 9: 65–75.
Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP (1997). Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17: 171–180.
Patneau DK, Mayer ML (1990). Structure-activity relationships for amino acid transmitter candidates acting at N-methyl-D-aspartate and quisqualate receptors. J Neurosci 10: 2385–2399.
Perea G, Navarrete M, Araque A (2009). Tripartite synapses: astrocytes process and control synaptic information. Trends Neurosci 32: 421–431.
Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW et al (1996). Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 16: 675–686.
Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D et al (1994). Localization of neuronal and glial glutamate transporters. Neuron 13: 713–725.
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE et al (2005). Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433: 73–77.
Saal D, Dong Y, Bonci A, Malenka RC (2003). Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37: 577–582.
Sari Y, Prieto AL, Barton SJ, Miller BR, Rebec GV (2010). Ceftriaxone-induced up-regulation of cortical and striatal GLT1 in the R6/2 model of Huntington's disease. J Biomed Sci 17: 62.
Schafe GE, LeDoux JE (2000). Memory consolidation of auditory pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J Neurosci 20: RC96.
Skucas VA, Mathews IB, Yang J, Cheng Q, Treister A, Duffy AM et al (2011). Impairment of select forms of spatial memory and neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4. J Neurosci 31: 6392–6397.
Strohschein S, Huttmann K, Gabriel S, Binder DK, Heinemann U, Steinhauser C (2011). Impact of aquaporin-4 channels on K+ buffering and gap junction coupling in the hippocampus. Glia 59: 973–980.
Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ et al (2011). Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144: 810–823.
Takano T, Kang J, Jaiswal JK, Simon SM, Lin JH, Yu Y et al (2005). Receptor-mediated glutamate release from volume sensitive channels in astrocytes. Proc Natl Acad Sci USA 102: 16466–16471.
Thrane AS, Rappold PM, Fujita T, Torres A, Bekar LK, Takano T et al (2011). Critical role of aquaporin-4 (AQP4) in astrocytic Ca2+ signaling events elicited by cerebral edema. Proc Natl Acad Sci USA 108: 846–851.
Tzingounis AV, Wadiche JI (2007). Glutamate transporters: confining runaway excitation by shaping synaptic transmission. Nat Rev Neurosci 8: 935–947.
Verkman AS (2005). More than just water channels: unexpected cellular roles of aquaporins. J Cell Sci 118: 3225–3232.
Wang ZY, Zhang YQ, Zhao ZQ (2006). Inhibition of tetanically sciatic stimulation-induced LTP of spinal neurons and Fos expression by disrupting glutamate transporter GLT-1. Neuropharmacology 51: 764–772.
Zeng XN, Sun XL, Gao L, Fan Y, Ding JH, Hu G (2007). Aquaporin-4 deficiency down-regulates glutamate uptake and GLT-1 expression in astrocytes. Mol Cell Neurosci 34: 34–39.
Zhang H, Verkman AS (2008). Aquaporin-4 independent Kir4.1 K+ channel function in brain glial cells. Mol Cell Neurosci 37: 1–10.
Zucker RS (1989). Short-term synaptic plasticity. Annu Rev Neurosci 12: 13–31.
Acknowledgements
We are grateful to Dr Gang Hu from Nanjing Medical University for supplying mice. This work was supported by grants from the Key Project of National Natural Science Foundation of China (NSFC No. 30930104) and NSFC grant (No. 81171258) to Dr JG Chen. It was also supported by the Program for New Century Excellent Talents in Universities of China (NCET-08-0225) and NSFC Grant (No. 81173039) to Dr F Wang.
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Li, YK., Wang, F., Wang, W. et al. Aquaporin-4 Deficiency Impairs Synaptic Plasticity and Associative Fear Memory in the Lateral Amygdala: Involvement of Downregulation of Glutamate Transporter-1 Expression. Neuropsychopharmacol 37, 1867–1878 (2012). https://doi.org/10.1038/npp.2012.34
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DOI: https://doi.org/10.1038/npp.2012.34
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