Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in γ-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (Tg) mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Lewis DA, Curley AA, Glausier JR, Volk DW . Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci 2012; 35: 57–67.
Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, Kanbara N, et al. Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 1997; 94: 6496–6499.
DeFelipe J, Lopez-Cruz PL, Benavides-Piccione R, Bielza C, Larranaga P, Anderson S, et al. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat Rev Neurosci 2013; 14: 202–216.
Ascoli GA, Alonso-Nanclares L, Anderson SA, Barrionuevo G, Benavides-Piccione R, Burkhalter A, et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat Rev Neurosci 2008; 9: 557–568.
Klausberger T, Somogyi P . Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 2008; 321: 53–57.
Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C . Interneurons of the neocortical inhibitory system. Nat Rev Neurosci 2004; 5: 793–807.
Lovett-Barron M, Turi GF, Kaifosh P, Lee PH, Bolze F, Sun XH, et al. Regulation of neuronal input transformations by tunable dendritic inhibition. Nat Neurosci 2012; 15: S421–S423.
Horvath S, Janka Z, Mirnics K . Analyzing schizophrenia by DNA microarrays. Biol Psychiatry 2010; 69: 157–162.
Schmidt MJ, Mirnics K . Neurodevelopment GABA system dysfunction, and schizophrenia. Neuropsychopharmacology 2015; 40: 190–206.
Faludi G, Mirnics K . Synaptic changes in the brain of subjects with schizophrenia. Int J Dev Neurosci 2011; 29: 305–309.
Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr, et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 1995; 52: 258–266.
Curley AA, Arion D, Volk DW, Asafu-Adjei JK, Sampson AR, Fish KN, et al. Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features. Am J Psychiatry 2011; 168: 921–929.
Guidotti A, Auta J, Davis JM, Di-Giorgi-Gerevini V, Dwivedi Y, Grayson DR, et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. Arch Gen Psychiatry 2000; 57: 1061–1069.
Hashimoto T, Arion D, Unger T, Maldonado-Aviles JG, Morris HM, Volk DW, et al. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 2008; 13: 147–161.
Schmidt MJ, Mirnics K . Modeling interneuron dysfunction in schizophrenia. Dev Neurosci 2012; 34: 152–158.
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: 6315–6326.
Garbett KA, Horvath S, Ebert PJ, Schmidt MJ, Lwin K, Mitchell A, et al. Novel animal models for studying complex brain disorders: BAC-driven miRNA-mediated in vivo silencing of gene expression. Mol Psychiatry 2010; 15: 987–995.
Brown JA, Horvath S, Garbett KA, Schmidt MJ, Everheart M, Gellert L, et al. The role of cannabinoid 1 receptor expressing interneurons in behavior. Neurobiol Dis 2013; 63: 210–221.
Schmidt MJ, Horvath S, Ebert P, Norris JL, Seeley EH, Brown J, et al. Modulation of behavioral networks by selective interneuronal inactivation. Mol Psychiatry 2013; 19: 580–587.
Belforte JE, Zsiros V, Sklar ER, Jiang Z, Yu G, Li Y, et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 2009; 13: 76–83.
Grunze HC, Rainnie DG, Hasselmo ME, Barkai E, Hearn EF, McCarley RW, et al. NMDA-dependent modulation of CA1 local circuit inhibition. J Neurosci 1996; 16: 2034–2043.
Li Q, Clark S, Lewis DV, Wilson WA . NMDA receptor antagonists disinhibit rat posterior cingulate and retrosplenial cortices: a potential mechanism of neurotoxicity. J Neurosci 2002; 22: 3070–3080.
Gong S, Yang XW . Modification of bacterial artificial chromosomes (BACs) and preparation of intact BAC DNA for generation of transgenic mice. Curr Protoc Neurosci 2005; Chapter 5, Unit 5.21; doi: 10.1002/0471142301.ns0521s31; PMID: 18428623..
Smith DR, Gallagher M, Stanton ME . Genetic background differences and nonassociative effects in mouse trace fear conditioning. Learn Mem 2007; 14: 597–605.
Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG . An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 2005; 122: 261–273.
Wozniak DF, Xiao M, Xu L, Yamada KA, Ornitz DM . Impaired spatial learning and defective theta burst induced LTP in mice lacking fibroblast growth factor 14. Neurobiol Dis 2007; 26: 14–26.
Gonzalez-Burgos G, Hashimoto T, Lewis DA . Alterations of cortical GABA neurons and network oscillations in schizophrenia. Curr Psychiatry Rep 2010; 12: 335–344.
Gonzalez-Burgos G, Lewis DA . NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia. Schizophr Bull 2012; 38: 950–957.
Lewis DA, Hashimoto T, Volk DW . Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312–324.
Braff DL, Geyer MA . Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry 1990; 47: 181–188.
Velasques B, Machado S, Paes F, Cunha M, Sanfim A, Budde H, et al. Sensorimotor integration and psychopathology: motor control abnormalities related to psychiatric disorders. World J Biol Psychiatry 2011; 12: 560–573.
Li L, Du Y, Li N, Wu X, Wu Y . Top-down modulation of prepulse inhibition of the startle reflex in humans and rats. Neurosci Biobehav Rev 2009; 33: 1157–1167.
Miralles C, Alonso Y, Verge B, Seto S, Gaviria AM, Moreno L, et al. Personality dimensions of schizophrenia patients compared to control subjects by gender and the relationship with illness severity. BMC Psychiatry 2014; 14: 151.
Reddy LF, Lee J, Davis MC, Altshuler L, Glahn DC, Miklowitz DJ, et al. Impulsivity and risk taking in bipolar disorder and schizophrenia. Neuropsychopharmacology 2013; 39: 456–463.
Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, et al. Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking. Nat Genet 1996; 12: 78–80.
Mrzljak L, Bergson C, Pappy M, Huff R, Levenson R, Goldman-Rakic PS . Localization of dopamine D4 receptors in GABAergic neurons of the primate brain. Nature 1996; 381: 245–248.
de Almeida J, Mengod G . D2 and D4 dopamine receptor mRNA distribution in pyramidal neurons and GABAergic subpopulations in monkey prefrontal cortex: implications for schizophrenia treatment. Neuroscience 2010; 170: 1133–1139.
Rotaru DC, Lewis DA, Gonzalez-Burgos G . The role of glutamatergic inputs onto parvalbumin-positive interneurons: relevance for schizophrenia. Rev Neurosci 23: 97–109.
Harrison PJ, Weinberger DR . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10: 40–68; image 45.
Benes FM, Berretta S . GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001; 25: 1–27.
Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML . Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol 2001; 41: 237–260.
Ren J, Xu H, Choi JK, Jenkins BG, Chen YI . Dopaminergic response to graded dopamine concentration elicited by four amphetamine doses. Synapse 2009; 63: 764–772.
Bhardwaj SK, Baharnoori M, Sharif-Askari B, Kamath A, Williams S, Srivastava LK . Behavioral characterization of dysbindin-1 deficient sandy mice. Behav Brain Res 2009; 197: 435–441.
Amann LC, Gandal MJ, Halene TB, Ehrlichman RS, White SL, McCarren HS, et al. Mouse behavioral endophenotypes for schizophrenia. Brain Res Bull 2010; 83: 147–161.
Neill JC, Barnes S, Cook S, Grayson B, Idris NF, McLean SL, et al. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism. Pharmacol Ther 2010; 128: 419–432.
Lahti AC, Koffel B, LaPorte D, Tamminga CA . Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 1995; 13: 9–19.
Driesen NR, McCarthy G, Bhagwagar Z, Bloch MH, Calhoun VD, D'Souza DC, et al. The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity. Neuropsychopharmacology 2013; 38: 2613–2622.
Coyle JT, Tsai G, Goff D . Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann NY Acad Sci 2003; 1003: 318–327.
Horvath S, Mirnics K . Schizophrenia as a Disorder of Molecular Pathways. Biol Psychiatry 2014; 77: 22–28.
Yi F, Ball J, Stoll KE, Satpute VC, Mitchell SM, Pauli JL, et al. Direct excitation of parvalbumin-positive interneurons by M1 muscarinic acetylcholine receptors: roles in cellular excitability, inhibitory transmission and cognition. J Physiol 2014; 592: 3463–3494.
Murray AJ, Sauer JF, Riedel G, McClure C, Ansel L, Cheyne L, et al. Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory. Nat Neurosci 2011; 14: 297–299.
Korotkova T, Fuchs EC, Ponomarenko A, von Engelhardt J, Monyer H . NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 2010; 68: 557–569.
Ouzir M . Impulsivity in schizophrenia: a comprehensive update. Aggress Viol Behav 2013; 18: 247–254.
Holt DJ, Weiss AP, Rauch SL, Wright CI, Zalesak M, Goff DC, et al. Sustained activation of the hippocampus in response to fearful faces in schizophrenia. Biol Psychiatry 2005; 57: 1011–1019.
Mukherjee P, Whalley HC, McKirdy JW, McIntosh AM, Johnstone EC, Lawrie SM, et al. Lower effective connectivity between amygdala and parietal regions in response to fearful faces in schizophrenia. Schizophr Res 2011; 134: 118–124.
Behere RV, Venkatasubramanian G, Arasappa R, Reddy NN, Gangadhar BN . First rank symptoms & facial emotion recognition deficits in antipsychotic naive schizophrenia: implications for social threat perception model. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35: 1653–1658.
Green MJ, Phillips ML . Social threat perception and the evolution of paranoia. Neurosci Biobehav Rev 2004; 28: 333–342.
Addington J, Addington D . Neurocognitive and social functioning in schizophrenia. Schizophr Bull 1999; 25: 173–182.
Swerdlow NR, Weber M, Qu Y, Light GA, Braff DL . Realistic expectations of prepulse inhibition in translational models for schizophrenia research. Psychopharmacology (Berl) 2008; 199: 331–388.
Giakoumaki SG . Cognitive and prepulse inhibition deficits in psychometrically high schizotypal subjects in the general population: relevance to schizophrenia research. J Int Neuropsychol Soc 2012; 18: 643–656.
Woodruff AR, McGarry LM, Vogels TP, Inan M, Anderson SA, Yuste R . State-dependent function of neocortical chandelier cells. J Neurosci 2011; 31: 17872–17886.
Woodruff AR, Anderson SA, Yuste R . The enigmatic function of chandelier cells. Front Neurosci 2010; 4: 201.
Javitt DC . Twenty-five years of glutamate in schizophrenia: are we there yet? Schizophr Bull 2012; 38: 911–913.
Gilani AI, Chohan MO, Inan M, Schobel SA, Chaudhury NH, Paskewitz S, et al. Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition. Proc Natl Acad Sci US A 2014; 111: 7450–7455.
Humby T, Wilkinson LS . Assaying dissociable elements of behavioural inhibition and impulsivity: translational utility of animal models. Curr Opin Pharmacol 2011; 11: 534–539.
Herrick CJ . Anatomical patterns and behavior patterns. Physiol Zool 1929; 2: 439–448.
Horvath S, Mirnics K . Immune system disturbances in schizophrenia. Biol Psychiatry 2013; 75: 316–323.
Michel M, Schmidt MJ, Mirnics K . Immune system gene dysregulation in autism and schizophrenia. Dev Neurobiol 2012; 72: 1277–1287.
Adam D . Mental health: on the spectrum. Nature 2013; 496: 416–418.
This work was supported by National Institutes of Health R01 MH067234 (to KM), R01 R21-MH103515 and K08 MH090412 (to SP) and by the NICHD P30 HD15052 grant awarded to the Vanderbilt Kennedy Center for Research on Human Development. JAB is supported by the 2T32MH065215-11 T32 NIH fellowship, whereas MJS was supported by the Vanderbilt Neuroscience Scholars Award. RB is supported by the generosity of Rosztoczy Foundation. We thank the Vanderbilt Murine Neurobehavioral Laboratory, especially Gregg Stanwood and John Allison, for consultation on behavioral tasks and equipment.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
About this article
Cite this article
Brown, J., Ramikie, T., Schmidt, M. et al. Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes. Mol Psychiatry 20, 1499–1507 (2015). https://doi.org/10.1038/mp.2014.192
This article is cited by
16p11.2 deletion mice exhibit compromised fronto-temporal connectivity, GABAergic dysfunction, and enhanced attentional ability
Communications Biology (2023)
BMC Biology (2022)
Nature Communications (2022)
Loss of Calretinin in L5a impairs the formation of the barrel cortex leading to abnormal whisker-mediated behaviors
Molecular Brain (2021)
Molecular Brain (2021)