Key Points
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GABAergic interneurons constitute the main elements that control excitability and shape oscillatory rhythms in the cerebral cortex. Multiple classes of interneuron exist, with similar but slightly divergent developmental trajectories.
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Disruption of the development or function of GABAergic interneurons in the cerebral cortex leads to epilepsy and may contribute to the emergence of specific symptoms of certain neuropsychiatric disorders, in particular those associated with cognitive impairment.
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Abnormal development of fast-spiking parvalbumin-expressing interneurons may predispose individuals to schizophrenia. Susceptibility genes for this disorder are thought to have a crucial role in the early development and wiring of this specific interneuron population.
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In autism spectrum disorders, disruption of the excitatory–inhibitory balance may occur in several neural systems, including the neocortex, the basal ganglia and the hindbrain. It is presently unclear whether such defects are caused by deficits in specific classes of interneuron.
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Increasing evidence indicates that abnormal GABAergic function is linked to several other neurological conditions, including Angelman's syndrome, fragile X syndrome and neurofibromatosis type I.
Abstract
Schizophrenia, autism and intellectual disabilities are best understood as spectrums of diseases that have broad sets of causes. However, it is becoming evident that these conditions also have overlapping phenotypes and genetics, which is suggestive of common deficits. In this context, the idea that the disruption of inhibitory circuits might be responsible for some of the clinical features of these disorders is gaining support. Recent studies in animal models demonstrate that the molecular basis of such disruption is linked to specific defects in the development and function of interneurons — the cells that are responsible for establishing inhibitory circuits in the brain. These insights are leading to a better understanding of the causes of schizophrenia, autism and intellectual disabilities, and may contribute to the development of more-effective therapeutic interventions.
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References
Klausberger, T. & Somogyi, P. Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 321, 53–57 (2008).
Maffei, A., Nataraj, K., Nelson, S. B. & Turrigiano, G. G. Potentiation of cortical inhibition by visual deprivation. Nature 443, 81–84 (2006).
Hensch, T. K. Critical period plasticity in local cortical circuits. Nature Rev. Neurosci. 6, 877–888 (2005).
Yizhar, O. et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011).
Haider, B., Duque, A., Hasenstaub, A. R. & McCormick, D. A. Neocortical network activity in vivo is generated through a dynamic balance of excitation and inhibition. J. Neurosci. 26, 4535–4545 (2006).
Dichter, M. A. & Ayala, G. F. Cellular mechanisms of epilepsy: a status report. Science 237, 157–164 (1987).
Kitamura, K. et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nature Genet. 32, 359–369 (2002).
Butt, S. J. et al. The requirement of Nkx2–1 in the temporal specification of cortical interneuron subtypes. Neuron 59, 722–732 (2008).
Galanopoulou, A. S. Mutations affecting GABAergic signaling in seizures and epilepsy. Pflugers Arch. 460, 505–523 (2010).
Poduri, A. & Lowenstein, D. Epilepsy genetics — past, present, and future. Curr. Opin. Genet. Dev. 21, 325–332 (2011).
Vogels, T. P. & Abbott, L. F. Gating multiple signals through detailed balance of excitation and inhibition in spiking networks. Nature Neurosci. 12, 483–491 (2009).
Klausberger, T. et al. Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo. Nature 421, 844–848 (2003).
Markram, H. et al. Interneurons of the neocortical inhibitory system. Nature Rev. Neurosci. 5, 793–807 (2004).
Freund, T. F. & Buzsáki, G. Interneurons of the hippocampus. Hippocampus 6, 347–470 (1996).
Ascoli, G. A. et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nature Rev. Neurosci. 9, 557–568 (2008).
Schumann, C. M., Bauman, M. D. & Amaral, D. G. Abnormal structure or function of the amygdala is a common component of neurodevelopmental disorders. Neuropsychologia 49, 745–759 (2011).
Simpson, E. H., Kellendonk, C. & Kandel, E. A possible role for the striatum in the pathogenesis of the cognitive symptoms of schizophrenia. Neuron 65, 585–596 (2010).
Somogyi, P. & Klausberger, T. Defined types of cortical interneurone structure space and spike timing in the hippocampus. J. Physiol. 562, 9–26 (2005).
Buzsaki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926–1929 (2004).
Gelman, D. M. & Marín, O. Generation of interneuron diversity in the mouse cerebral cortex. Eur. J. Neurosci. 31, 2136–2141 (2010).
Batista-Brito, R. & Fishell, G. The developmental integration of cortical interneurons into a functional network. Curr. Top. Dev. Biol. 87, 81–118 (2009).
Wonders, C. P. & Anderson, S. A. The origin and specification of cortical interneurons. Nature Rev. Neurosci. 7, 687–696 (2006).
Lewis, D. A. & Levitt, P. Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci. 25, 409–432 (2002). A general overview of the evidence that supports the idea that schizophrenia is a consequence of abnormal brain development.
Walsh, C. A., Morrow, E. M. & Rubenstein, J. L. Autism and brain development. Cell 135, 396–400 (2008).
Lewis, D. A., Cruz, D., Eggan, S. & Erickson, S. Postnatal development of prefrontal inhibitory circuits and the pathophysiology of cognitive dysfunction in schizophrenia. Ann. NY Acad. Sci. 1021, 64–76 (2004).
Elvevag, B. & Goldberg, T. E. Cognitive impairment in schizophrenia is the core of the disorder. Crit. Rev. Neurobiol. 14, 1–21 (2000).
Sitskoorn, M. M., Aleman, A., Ebisch, S. J., Appels, M. C. & Kahn, R. S. Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophr. Res. 71, 285–295 (2004).
Park, S. & Holzman, P. S. Schizophrenics show spatial working memory deficits. Arch. Gen. Psychiatry 49, 975–982 (1992).
Uhlhaas, P. J. & Singer, W. Abnormal neural oscillations and synchrony in schizophrenia. Nature Rev. Neurosci. 11, 100–113 (2010).
Farzan, F. et al. Evidence for gamma inhibition deficits in the dorsolateral prefrontal cortex of patients with schizophrenia. Brain 133, 1505–1514 (2010).
Lewis, D. A., Hashimoto, T. & Volk, D. W. Cortical inhibitory neurons and schizophrenia. Nature Rev. Neurosci. 6, 312–324 (2005).
Yoon, J. H. et al. GABA concentration is reduced in visual cortex in schizophrenia and correlates with orientation-specific surround suppression. J. Neurosci. 30, 3777–3781 (2010).
Ongur, D., Prescot, A. P., McCarthy, J., Cohen, B. M. & Renshaw, P. F. Elevated γ-aminobutyric acid levels in chronic schizophrenia. Biol. Psychiatry 68, 667–670 (2010).
Constantinidis, C., Williams, G. V. & Goldman-Rakic, P. S. A role for inhibition in shaping the temporal flow of information in prefrontal cortex. Nature Neurosci. 5, 175–180 (2002).
Rao, S. G., Williams, G. V. & Goldman-Rakic, P. S. Destruction and creation of spatial tuning by disinhibition: GABAA blockade of prefrontal cortical neurons engaged by working memory. J. Neurosci. 20, 485–494 (2000).
Benes, F. M., McSparren, J., Bird, E. D., SanGiovanni, J. P. & Vincent, S. L. Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch. Gen. Psychiatry 48, 996–1001 (1991).
Benes, F. M. & Berretta, S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25, 1–27 (2001).
Akbarian, S. et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch. Gen. Psychiatry 52, 258–266 (1995).
Hashimoto, T. et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J. Neurosci. 23, 6315–6326 (2003).
Lisman, J. E. et al. Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci. 31, 234–242 (2008).
Lewis, D. A. & Sweet, R. A. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. J. Clin. Invest. 119, 706–716 (2009).
Haenschel, C. et al. Cortical oscillatory activity is critical for working memory as revealed by deficits in early-onset schizophrenia. J. Neurosci. 29, 9481–9489 (2009).
Barr, M. S. et al. Evidence for excessive frontal evoked gamma oscillatory activity in schizophrenia during working memory. Schizophr. Res. 121, 146–152 (2010).
Woo, T. U., Whitehead, R. E., Melchitzky, D. S. & Lewis, D. A. A subclass of prefrontal γ-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc. Natl Acad. Sci. USA 95, 5341–5346 (1998).
Grunze, H. C. et al. NMDA-dependent modulation of CA1 local circuit inhibition. J. Neurosci. 16, 2034–2043 (1996).
Gunduz-Bruce, H. The acute effects of NMDA antagonism: from the rodent to the human brain. Brain Res. Rev. 60, 279–286 (2009).
Carlen, M. et al. A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Mol. Psychiatry 5 Apr 2011 (doi:10.1038/mp.2011.31).
Korotkova, T., Fuchs, E. C., Ponomarenko, A., von Engelhardt, J. & Monyer, H. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 68, 557–569 (2010).
Belforte, J. E. et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nature Neurosci. 13, 76–83 (2010). This study shows that early postnatal deletion of the gene encoding the NR1 subunit of the NMDA receptor from PV+ fast-spiking interneurons in the cortex is enough to trigger schizophrenia-related symptoms in mice.
Runyan, C. A. et al. Response features of parvalbumin-expressing interneurons suggest precise roles for subtypes of inhibition in visual cortex. Neuron 67, 847–857 (2010).
Keverne, E. B. GABA-ergic neurons and the neurobiology of schizophrenia and other psychoses. Brain Res. Bull. 48, 467–473 (1999). This is one of the first articles in which the abnormal development of GABAergic cells was suggested to be linked to schizophrenia.
Fazzari, P. et al. Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling. Nature 464, 1376–1380 (2010). This study demonstrates that the loss of ERBB4 signalling impairs the formation of axon terminals by chandelier cells and reduces the number of excitatory synapses that cortical PV+ interneurons receive.
Vullhorst, D. et al. Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. J. Neurosci. 29, 12255–12264 (2009).
Yau, H. J., Wang, H. F., Lai, C. & Liu, F. C. Neural development of the neuregulin receptor ErbB4 in the cerebral cortex and the hippocampus: preferential expression by interneurons tangentially migrating from the ganglionic eminences. Cereb. Cortex 13, 252–264 (2003).
Flames, N. et al. Short- and long-range attraction of cortical GABAergic interneurons by neuregulin-1. Neuron 44, 251–261 (2004).
Ting, A. K. et al. Neuregulin 1 promotes excitatory synapse development and function in GABAergic interneurons. J. Neurosci. 31, 15–25 (2011). This study supports the idea that NRG1–ERBB4 signalling is required for the formation of excitatory synapses onto PV+ interneurons.
Wen, L. et al. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc. Natl Acad. Sci. USA 107, 1211–1216 (2010). In this study, the authors show that deletion of Erbb4 from PV+ neurons in mice leads to increased activity of pyramidal cells and behavioural abnormalities.
Mei, L. & Xiong, W. C. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nature Rev. Neurosci. 9, 437–452 (2008).
Harrison, P. J. & Law, A. J. Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol. Psychiatry 60, 132–140 (2006).
Stefansson, H. et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am. J. Hum. Genet. 72, 83–87 (2003). This study reports the first genetic link between NRG1 and schizophrenia.
Marenco, S. et al. Genetic association of ErbB4 and human cortical GABA levels in vivo. J. Neurosci. 31, 11628–11632 (2011).
Millar, J. K. et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet. 9, 1415–1423 (2000).
Porteous, D. J., Millar, J. K., Brandon, N. J. & Sawa, A. DISC1 at 10: connecting psychiatric genetics and neuroscience. Trends Mol. Med. 17, 699–706 (2011).
Hikida, T. et al. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc. Natl Acad. Sci. USA 104, 14501–14506 (2007). This article reports on several phenotypes caused by the expression of a disease-associated form of DISC1 . These phenotypes include cortical interneuron abnormalities.
Niwa, M. et al. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron 65, 480–489 (2010).
Ottis, P. et al. Convergence of two independent mental disease genes on the protein level: recruitment of dysbindin to cell-invasive disrupted-in-schizophrenia 1 aggresomes. Biol. Psychiatry 70, 604–610 (2011).
Straub, R. E. et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am. J. Hum. Genet. 71, 337–348 (2002).
Ji, Y. et al. Role of dysbindin in dopamine receptor trafficking and cortical GABA function. Proc. Natl Acad. Sci. USA 106, 19593–19598 (2009). This study demonstrates a link between dysbindin and the normal functioning of cortical PV+ interneurons.
Weickert, C. S. et al. Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. Arch. Gen. Psychiatry 61, 544–555 (2004).
Talbot, K. et al. Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J. Clin. Invest. 113, 1353–1363 (2004).
Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007).
Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999). This study reveals that Rett's syndrome is primarily caused by mutations in MECP2.
Guy, J., Cheval, H., Selfridge, J. & Bird, A. The role of MeCP2 in the brain. Annu. Rev. Cell. Dev. Biol. 27, 631–652 (2010).
Guy, J., Hendrich, B., Holmes, M., Martin, J. E. & Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nature Genet. 27, 322–326 (2001).
Chen, R. Z., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nature Genet. 27, 327–331 (2001).
Chao, H. T. et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010). This elegant genetic dissection of the role of MECP2 in GABAergic neurons shows that deficits in forebrain interneurons might underlie many of the symptoms that are observed in Rett's syndrome.
Fyffe, S. L. et al. Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron 59, 947–958 (2008).
Samaco, R. C. et al. Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities. Proc. Natl Acad. Sci. USA 106, 21966–21971 (2009).
Adachi, M., Autry, A. E., Covington, H. E. & Monteggia, L. M. MeCP2-mediated transcription repression in the basolateral amygdala may underlie heightened anxiety in a mouse model of Rett syndrome. J. Neurosci. 29, 4218–4227 (2009).
Gemelli, T. et al. Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol. Psychiatry 59, 468–476 (2006).
Zhang, L., He, J., Jugloff, D. G. & Eubanks, J. H. The MeCP2-null mouse hippocampus displays altered basal inhibitory rhythms and is prone to hyperexcitability. Hippocampus 18, 294–309 (2008).
Medrihan, L. et al. Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome. J. Neurophysiol. 99, 112–121 (2008).
Dani, V. S. et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 102, 12560–12565 (2005).
Martinowich, K. et al. DNA methylation-related chromatin remodeling in activity-dependent Bdnf gene regulation. Science 302, 890–893 (2003).
Huang, Z. J., Di Cristo, G. & Ango, F. Development of GABA innervation in the cerebral and cerebellar cortices. Nature Rev. Neurosci. 8, 673–686 (2007).
State, M. W. The genetics of child psychiatric disorders: focus on autism and Tourette syndrome. Neuron 68, 254–269 (2010).
Kim, H. G. et al. Disruption of neurexin 1 associated with autism spectrum disorder. Am. J. Hum. Genet. 82, 199–207 (2008).
Abrahams, B. S. & Geschwind, D. H. Advances in autism genetics: on the threshold of a new neurobiology. Nature Rev. Genet. 9, 341–355 (2008).
Laumonnier, F. et al. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am. J. Hum. Genet. 74, 552–557 (2004).
Jamain, S. et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genet. 34, 27–29 (2003).
Sudhof, T. C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008).
Chih, B., Engelman, H. & Scheiffele, P. Control of excitatory and inhibitory synapse formation by neuroligins. Science 307, 1324–1328 (2005).
Huang, Z. J. & Scheiffele, P. GABA and neuroligin signaling: linking synaptic activity and adhesion in inhibitory synapse development. Curr. Opin. Neurobiol. 18, 77–83 (2008).
Tabuchi, K. et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71–76 (2007).
Moessner, R. et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am. J. Hum. Genet. 81, 1289–1297 (2007).
Durand, C. M. et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genet. 39, 25–27 (2007).
Peca, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011). An analysis of Shank3 -null mouse mutants that reveals that striatal dysfunction is probably involved in the emergence of some of the neurological symptoms of autism.
Strauss, K. A. et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. New Engl. J. Med. 354, 1370–1377 (2006).
Alarcon, M. et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am. J. Hum. Genet. 82, 150–159 (2008).
Arking, D. E. et al. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 82, 160–164 (2008).
Bakkaloglu, B. et al. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am. J. Hum. Genet. 82, 165–173 (2008).
Vernes, S. C. et al. A functional genetic link between distinct developmental language disorders. New Engl. J. Med. 359, 2337–2345 (2008).
Poliak, S. & Peles, E. The local differentiation of myelinated axons at nodes of Ranvier. Nature Rev. Neurosci. 4, 968–980 (2003).
Scott- Van Zeeland, A. A. et al. Altered functional connectivity in frontal lobe circuits is associated with variation in the autism risk gene CNTNAP2. Sci. Transl. Med. 2, 56ra80 (2010).
Penagarikano, O. et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147, 235–246 (2011). This study shows that mice with mutations in Cntnap2 have anatomical, functional and behavioural deficits that resemble those that are seen in humans with mutations in this gene. The authors also report that these mice have cortical interneuron deficits, which suggests that CNTNAP2 has a role in interneuron development.
Miura, K. et al. Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. Neurobiol. Dis. 9, 149–159 (2002).
Kishino, T., Lalande, M. & Wagstaff, J. UBE3A/E6-AP mutations cause Angelman syndrome. Nature Genet. 15, 70–73 (1997).
Jiang, Y. H. et al. Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3. PLoS ONE 5, e12278 (2010).
Homanics, G. E. et al. Mice devoid of γ-aminobutyrate type A receptor β3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Natl Acad. Sci. USA 94, 4143–4148 (1997).
Egawa, K. et al. Aberrant somatosensory-evoked responses imply GABAergic dysfunction in Angelman syndrome. NeuroImage 39, 593–599 (2008).
Olmos-Serrano, J. L. et al. Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J. Neurosci. 30, 9929–9938 (2010).
Gibson, J. R., Bartley, A. F., Hays, S. A. & Huber, K. M. Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J. Neurophysiol. 100, 2615–2626 (2008).
Curia, G., Papouin, T., Seguela, P. & Avoli, M. Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. Cereb. Cortex 19, 1515–1520 (2009).
Centonze, D. et al. Abnormal striatal GABA transmission in the mouse model for the fragile X syndrome. Biol. Psychiatry 63, 963–973 (2008).
Penagarikano, O., Mulle, J. G. & Warren, S. T. The pathophysiology of fragile X syndrome. Annu. Rev. Genom. Hum. Genet. 8, 109–129 (2007).
Selby, L., Zhang, C. & Sun, Q. Q. Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein. Neurosci. Lett. 412, 227–232 (2007).
D'Hulst, C. & Kooy, R. F. The GABAA receptor: a novel target for treatment of fragile X? Trends Neurosci. 30, 425–431 (2007).
Bear, M. F., Huber, K. M. & Warren, S. T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377 (2004).
Lott, I. T. & Dierssen, M. Cognitive deficits and associated neurological complications in individuals with Down's syndrome. Lancet Neurol. 9, 623–633 (2010).
Reeves, R. H. et al. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nature Genet. 11, 177–184 (1995).
Belichenko, P. V. et al. Excitatory–inhibitory relationship in the fascia dentata in the Ts65Dn mouse model of Down syndrome. J. Comp. Neurol. 512, 453–466 (2009).
Kleschevnikov, A. M. et al. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J. Neurosci. 24, 8153–8160 (2004).
Shilyansky, C., Lee, Y. S. & Silva, A. J. Molecular and cellular mechanisms of learning disabilities: a focus on NF1. Annu. Rev. Neurosci. 33, 221–243 (2010).
Costa, R. M. et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415, 526–530 (2002).
Cui, Y. et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 135, 549–560 (2008).
Tsuang, M. T., Stone, W. S. & Faraone, S. V. Genes, environment and schizophrenia. Br. J. Psychiatry 40, s18–s24 (2001).
Brown, A. S. The environment and susceptibility to schizophrenia. Prog. Neurobiol. 93, 23–58 (2011).
Urdinguio, R. G., Sanchez-Mut, J. V. & Esteller, M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol. 8, 1056–1072 (2009).
Semple, D. M., McIntosh, A. M. & Lawrie, S. M. Cannabis as a risk factor for psychosis: systematic review. J. Psychopharm. 19, 187–194 (2005).
Wobrock, T. et al. Increased cortical inhibition deficits in first-episode schizophrenia with comorbid cannabis abuse. Psychopharmacology 208, 353–363 (2010).
Puighermanal, E. et al. Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nature Neurosci. 12, 1152–1158 (2009).
Katona, I. & Freund, T. F. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nature Med. 14, 923–930 (2008).
Berghuis, P. et al. Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science 316, 1212–1216 (2007).
Geddes, J. R. & Lawrie, S. M. Obstetric complications and schizophrenia: a meta-analysis. Br. J. Psychiatry 167, 786–793 (1995).
Tyzio, R. et al. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science 314, 1788–1792 (2006).
Smith, S. E., Li, J., Garbett, K., Mirnics, K. & Patterson, P. H. Maternal immune activation alters fetal brain development through interleukin-6. J. Neurosci. 27, 10695–10702 (2007).
Behrens, M. M., Ali, S. S. & Dugan, L. L. Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J. Neurosci. 28, 13957–13966 (2008). This study delineates a molecular pathway that might help us to understand the induction of schizophrenia-like behaviours by NMDA agonists, such as ketamine.
Behrens, M. M. et al. Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 318, 1645–1647 (2007).
Uhlhaas, P. J., Roux, F., Rodriguez, E., Rotarska-Jagiela, A. & Singer, W. Neural synchrony and the development of cortical networks. Trends Cogn. Sci. 14, 72–80 (2010).
Low, N. C. & Hardy, J. What is a schizophrenic mouse? Neuron 54, 348–349 (2007).
Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007).
Giacometti, E., Luikenhuis, S., Beard, C. & Jaenisch, R. Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proc. Natl Acad. Sci. USA 104, 1931–1936 (2007).
Tropea, D. et al. Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc. Natl Acad. Sci. USA 106, 2029–2034 (2009).
Shu, Y., Hasenstaub, A. & McCormick, D. A. Turning on and off recurrent balanced cortical activity. Nature 423, 288–293 (2003).
Shadlen, M. N. & Newsome, W. T. Noise, neural codes and cortical organization. Curr. Opin. Neurobiol. 4, 569–579 (1994).
Olshausen, B. A., Anderson, C. H. & Van Essen, D. C. A neurobiological model of visual attention and invariant pattern recognition based on dynamic routing of information. J. Neurosci. 13, 4700–4719 (1993).
Vogels, T. P. & Abbott, L. F. Signal propagation and logic gating in networks of integrate-and-fire neurons. J. Neurosci. 25, 10786–10795 (2005).
Kremkow, J., Aertsen, A. & Kumar, A. Gating of signal propagation in spiking neural networks by balanced and correlated excitation and inhibition. J. Neurosci. 30, 15760–15768 (2010).
Cline, H. Synaptogenesis: a balancing act between excitation and inhibition. Curr. Biol. 15, R203–R205 (2005).
Roberts, E. Prospects for research on schizophrenia. An hypotheses suggesting that there is a defect in the GABA system in schizophrenia. Neurosci. Res. Program. Bull. 10, 468–482 (1972).
Benes, F. M., Vincent, S. L., Marie, A. & Khan, Y. Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience 75, 1021–1031 (1996).
Benes, F. M., Vincent, S. L., Alsterberg, G., Bird, E. D. & SanGiovanni, J. P. Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J. Neurosci. 12, 924–929 (1992).
Selemon, L. D., Rajkowska, G. & Goldman-Rakic, P. S. Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch. Gen. Psychiatry 52, 805–820 (1995).
Daviss, S. R. & Lewis, D. A. Local circuit neurons of the prefrontal cortex in schizophrenia: selective increase in the density of calbindin-immunoreactive neurons. Psychiatry Res. 59, 81–96 (1995).
Rubenstein, J. L. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).
Hussman, J. P. Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism. J. Autism. Dev. Disord. 31, 247–248 (2001).
Fatemi, S. H. et al. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol. Psychiatry 52, 805–810 (2002).
Oblak, A. L., Gibbs, T. T. & Blatt, G. J. Reduced GABAA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. Brain Res. 1380, 218–228 (2010).
Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008).
Law, A. J., Kleinman, J. E., Weinberger, D. R. & Weickert, C. S. Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. Hum. Mol. Genet. 16, 129–141 (2007).
Neddens, J. & Buonanno, A. Selective populations of hippocampal interneurons express ErbB4 and their number and distribution is altered in ErbB4 knockout mice. Hippocampus 20, 724–744 (2010).
Fisahn, A., Neddens, J., Yan, L. & Buonanno, A. Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia. Cereb. Cortex 19, 612–618 (2009).
Volk, D., Austin, M., Pierri, J., Sampson, A. & Lewis, D. GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. Am. J. Psychiatry 158, 256–265 (2001).
Volk, D. W. et al. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb. Cortex 12, 1063–1070 (2002).
Garey, L. J. et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J. Neurol. Neurosurg. Psychiatry 65, 446–453 (1998).
Glantz, L. A. & Lewis, D. A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65–73 (2000).
Radyushkin, K. et al. Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit. Genes Brain Behav. 8, 416–425 (2009).
Chadman, K. K. et al. Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res. 1, 147–158 (2008).
Jamain, S. et al. Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc. Natl Acad. Sci. USA 105, 1710–1715 (2008).
Etherton, M. R., Blaiss, C. A., Powell, C. M. & Südhof, T. C. Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc. Natl Acad. Sci. USA 106, 17998–18003 (2009).
Chen, Y. J. et al. Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. J. Neurosci. 28, 6872–6883 (2008).
Acknowledgements
I would like to thank M. Maravall and B. Rico for their thoughtful comments on earlier versions of this manuscript, M. Sefton for editorial assistance and the many colleagues who have shared their thoughts on this topic, including all the members of my laboratory. Our work is supported by grants from the Spanish Ministry of Science and Innovation (SAF2008-00770, SAF2009-08049-E and CONSOLIDER CSD2007-00023), the Brain and Behaviour Research Foundation (NARSAD) and the Fundació La Marató.
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Glossary
- Pyramidal cells
-
Pyramidal cells are the principal neurons of the cerebral cortex — constituting ∼80% of the total number of neurons in this brain region — and use glutamate as a neurotransmitter.
- GABAergic interneurons
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GABAergic interneurons have diverse morphologies but are typically aspiny and localized to the cerebral cortex. They constitute ∼20% of the total number of neurons in this region.
- Axon initial segment
-
(AIS). The axon initial segment is the proximal end of the axon, close to the neuron soma, and is where action potentials are generated.
- Oscillatory activity
-
Oscillatory activity comprises rhythmic or repetitive neural activity that enables coordinated activity during normal brain functioning.
- Gamma-frequency
-
The gamma frequency constitutes a type of neural oscillation and occurs at a prototypical frequency of approximately 40 Hz, although it may range from 30 to 80 Hz.
- Forebrain
-
The forebrain is the most anterior region of the brain and includes the diencephalon as well as the telencephalon. The basal ganglia, the amygdala and the cerebral cortex are all parts of the telencephalon.
- Cannabis
-
Cannabis is a genus of plants that contain high levels of Δ9-tetrahydrocannabinol, a psychoactive substance that acts as a partial agonist of cannabinoid receptors in the brain and that is responsible for the stimulating effect that is associated with cannabis-derived drugs.
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Marín, O. Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci 13, 107–120 (2012). https://doi.org/10.1038/nrn3155
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DOI: https://doi.org/10.1038/nrn3155
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