Modeling Interneuron Dysfunction in Schizophrenia

Dev Neurosci DOI: 10.1159/000336731

Published online: May 8, 2012

Modeling Interneuron Dysfunction in Schizophrenia Martin J. Schmidt Karoly Mirnics Department of Psychiatry, Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tenn., USA

Key Words Schizophrenia ⴢ Gene expression ⴢ GAD67 ⴢ Interneurons ⴢ Mouse behavior

Abstract Schizophrenia is a debilitating neurodevelopmental disorder affecting approximately 1% of the population and imposing a significant burden on society. One of the most replicated and well-established postmortem findings is a deficit in the expression of the gene encoding the 67-kDa isoform of glutamic acid decarboxylase (GAD67), the primary GABA-producing enzyme in the brain. GAD67 is expressed in various classes of interneurons, with vastly different morphological, molecular, and physiological properties. Importantly, GABA system deficits in schizophrenia encompass multiple interneuronal subtypes, raising several important questions. First, do different classes of interneurons regulate different aspects of behavior? Second, can we model cell-type-specific GABAergic deficits in mice, and will the rodent findings translate to human physiology? Finally, will this knowledge open the door to knowledgebased approaches to treat schizophrenia? Copyright © 2012 S. Karger AG, Basel

Introduction

Schizophrenia is a debilitating disorder affecting approximately 1% of the population [1]. Its symptoms fall into three domains: positive symptoms including hallu© 2012 S. Karger AG, Basel 0378–5866/12/0000–0000$38.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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cinations and delusions, negative symptoms including social withdrawal, anhedonia, and avolition among others, and cognitive symptoms including deficits in working memory, disorganized thought, and attention. The cause(s) of schizophrenia remain(s) elusive although genetic and environmental disruptions in neurodevelopment remain a consistent focus [2, 3]. Patients typically first experience symptoms in adolescence or early adulthood and as many as 60% experience impairment throughout life [4]. In addition to the behavioral impact, cardiovascular disease and metabolic syndromes, including weight gain and diabetes, contribute to a mortality rate that is 2.5 times higher than the general population [5–7]. The duration and severity of the illness represent a significant burden to the patient, his/her family, the health care system, and society at large. In fact, the World Health Organization ranks schizophrenia as the third most costly neuropsychiatric illness behind only unipolar depression and alcohol abuse [8]. The financial and personal toll of the illness reaches from patient to population and working towards a better understanding of its development will enable more effective treatments that alleviate that strain. Two people who have influenced schizophrenia research and treatment from the beginning had different interpretations of its origin. Emil Kraepelin referred to it as dementia praecox linking it to other dementias with defined neuropathology like Alzheimer’s dementia. He was convinced that schizophrenia was a disorder of the brain and devoted himself to looking for pathogens and/ Martin J. Schmidt 8128 Medical Research Building III 465 21st Avenue South Nashville, TN 37232-8548 (USA) Tel. +1 615 936 2014, E-Mail martin.j.schmidt @ vanderbilt.edu

or pathology that might explain its symptoms [9]. In contrast, Eugen Bleuler described it as schizophrenia, or ‘split mind’, and believed connecting with patients individually was more beneficial to understanding the illness than studying neurobiology [10]. Psychosis, the defining feature of schizophrenia, is impairment in distinguishing reality amongst hallucinations and delusions. This presents a problem for researchers interested in mental illness. Is it possible to quantify reality and study its neurobiology scientifically? Interestingly, a revolution in experimental psychology was taking place at about the same time Kraepelin and Bleuler were consolidating their observations. J.B. Watson [11] detailed his displeasure with the existing study of the mind in an article published in 1913. In his view, psychological processes can be studied as a science only when subjective processes of introspection, consciousness, and the mind are excluded [11]. Watson’s ‘behaviorism’ would later be extended by scientists like B.F. Skinner to incorporate those complicated ‘internal’ processes that have quantifiable outcomes such as value judgments, motivation, and decision-making, which are now also thought to be dysfunctional in schizophrenia. No causal pathology exists for schizophrenia [12]. However, alterations in neural connectivity and gene expression are being identified and advances in molecular biology have made it possible to tease apart the meaning of these insults in animal models. Although we will never recapitulate psychosis in any model, incorporating classical views of schizophrenia and behavior with modern molecular biology allows for the empirical analysis of molecular genetic dysfunction, its effects on the brain, and on behavior.

GABA-Associated Deficits in Schizophrenia

Discovering that GABA controls dopamine release in striatal and mesolimbic circuits prompted researchers in the 1970s to theorize that GABA dysfunction could cause schizophrenia [13, 14]. GABA-associated deficits emerged in the clinical literature with the publication of studies that found reduced GABA content [15], increased GABA receptor subunit protein levels [16, 17] but decreased receptor mRNA [18], decreased GABA transporter [19] protein levels, and altered interneuron densities [20–22]. In 1995, Akbarian et al. [23] published the first studies of gene expression in postmortem schizophrenic brain tissue and found a decrease in the 67-kDa isoform of glutamic acid decarboxylase (GAD67) mRNA in the prefrontal cortex that cell loss could not account for. GAD67 2

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is the primary enzyme responsible for the production of GABA in the brain [24]. The GAD67 expression deficit has become one of the most consistently replicated gene expression findings in schizophrenia across many different brain regions, patient cohorts, methods, and investigators, which is remarkable given the complex genetics and diverse presentation of symptoms seen in patients [25–35]. How might this deficit develop? Several studies of the gene that encodes GAD67, GAD1, have yielded a number of single-nucleotide polymorphisms that are found more frequently in schizophrenic patients than controls [36– 38]. The majority of single-nucleotide polymorphisms in each study was found in gene regulatory sequences suggesting a role in regulating gene expression and not protein function. An analysis of patients with a GAD1 genetic variant suggested that DNA sequence variation can effectively regulate mRNA expression levels in the postmortem tissue of subjects with schizophrenia [36]. A second mechanism that may contribute to decreased GAD67 expression in schizophrenia is epigenetics. Genes can be suppressed when promoters or other regulatory sequences are methylated causing changes in chromatin structure that prevent transcription [39]. Methylation is carried out by enzymes such as DNMT1 which is overexpressed in GABAergic interneurons of schizophrenic patients and correlated with decreased GAD67 mRNA in the same cells suggesting dysfunctional epigenetic regulation of the gene; however, a causal relationship between increased DNMT1 and GAD1 promoter methylation has not been established conclusively in postmortem studies [39–43]. Finally, it has been suggested recently that GAD67 downregulation and other GABA-associated dysfunction measured in postmortem tissue collectively reflect general dysfunction of GABA system development via changes in cell cycle regulation [44], impairments in interneuron maturation [45], and migration defects [20, 46]. The fact that several different mechanisms can lead to decreases in GAD67 gene expression argues that diverse insults and influences can converge, giving rise to a common GABAergic dysfunction.

Modeling GABAergic Deficits in Animal Models

Based on the postmortem data, it is clear that alterations in the GABAergic system are hallmark features of schizophrenia. However, postmortem studies leave two important questions unanswered. First, what part does GAD67 play in the pathophysiology of schizophrenia, Schmidt/Mirnics

and is this related to altered behavior? Second, do different classes of interneurons regulate different aspects of behavior? Since solutions cannot easily be determined in humans, animal models are developed to address these questions empirically. Animal models offer the ability to study the causal influence of genetic and environmental manipulations at different developmental stages on cellular, molecular, and behavioral processes and have provided insight into potential mechanisms of GABA system dysfunction in human disorders. GABAergic cell types are so diverse that creating a nomenclature for their defining characteristics continues to be a tedious task, but they can be broadly categorized based on morphological, molecular, and physiological properties [47]. Classification is important because subtypes of interneurons are involved in regulating different aspects of pyramidal cell function and are concentrated in brain regions that mediate different behaviors [25, 48–51]. For example, parvalbumin (PV), neuropeptide Y, and cholecystokinin (CCK) are molecular markers of distinct interneuron populations [49]. PV-positive chandelier cells synapse on the axon initial segments and basket cells regulate the cell soma of pyramidal cells, regulating output and integration across multiple cortical and subcortical areas [52–54]. In contrast, CCK-positive basket cells regulate inhibition of pyramidal cell soma directly via synaptic transmission and indirectly via modulation of other interneurons primarily in limbic and frontal circuits [55–59]. Furthermore, neuropeptide-Y-positive neurogliaform and Martinotti interneurons release GABA via volume transmission [60] and inhibit pyramidal cell distal dendrites [61] in diffuse cortical regions, the striatum, hippocampus, amygdala, and hypothalamus [50, 52, 61–63]. All of these different cell types appear to be affected in schizophrenia [21, 25, 30, 32, 33, 46], but their contribution to the disease symptomatology remains largely unknown. Therefore, dysfunction of particular classes of interneurons could generate diverse pathophysiology and behavior. For example, PV-positive chandelier cells appear to control ␥-oscillations in the brain, which are believed to be linked to working memory [25] while CCK-positive cells may play a role in integrating neuromodulatory information and fine-tune network activity underlying mood [59]. To systematically tease out the cell-type-specific interneuronal contribution to behavioral processes, our laboratory has recently developed several novel mouse models that downregulate GAD67 in specific classes of interneurons [64]. Using a synthetic miRNA, GAD67 was downregulated in CCK-positive, neuropeptide-Y-positive, PVpositive and CNR1-positive interneurons using BAC-driv-

en, fluorescent constructs. In the targeted cell populations of the transgenic animals, GAD67 expression was abolished by 70–95%, but without a seizure phenotype. Preliminary data indicate that the tested interneuronal cell types regulate different, well-defined physiological and behavioral processes. Therefore, we argue that future therapeutic interventions directed toward restoring the function of specific interneuronal cell types might be a promising approach to developing conceptually novel, knowledge-based therapies of schizophrenia, geared toward alleviating the most debilitating symptoms of the disease. There are two important caveats that must be acknowledged when comparing the development of GABAergic circuitry in human and mouse. First, the proportion of interneurons to pyramidal cells in the human cortex is much greater than in the mouse [65]. This discrepancy also raises the possibility that interneuron deficits in human could have more robust effects on behavior than what is seen in the transgenic rodent models. Second, up to 65% of human cortical interneurons arise from an alternate source of progenitors in the neocortical ventricular and subventricular zone that may have developed during primate evolution [66]. Regardless of these caveats, rodent models to assess the differentiation and migration of GABAergic interneurons from the ganglionic eminences [67–69] are very informative about the neurobiological processes underlying the developmental aspects of schizophrenia. For example, dopamine [70], cannabinoids [71] and multiple schizophrenia susceptibility genes [72, 73] play roles in regulating interneuron migration and synapse formation during development in mice and may contribute to GABA system developmental disturbances in schizophrenia [46, 74–76]. Complementing the genetic population-based studies and expression/epigenetic data from postmortem research, the use of animal models is also able to shed light on the mechanisms by which GAD67 alters normal brain function. Data from rodent models suggest that GAD67 expression can be reduced by chronic dopamine D2 receptor stimulation [77, 78] or acute NMDA receptor antagonism [79] in multiple brain regions. These data mirror the ability of chronic dopamine stimulation [80] and acute NMDA receptor antagonism [81, 82] to precipitate psychosis in humans. Thus, the NMDA hypofunction hypothesis, the dopamine hypothesis, and the GABA dysfunction hypothesis of schizophrenia could be integrated with GAD67 deficiency being a player in each [29]. Furthermore, some antipsychotic drugs demethylate the GAD1 promoter which may enhance their therapeutic profile in some cases [83, 84]. According to one study, treating mice

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with nicotine suppressed DNMT1 expression, demethylated the GAD1 promoter, and increased GAD67 protein levels which may explain in part the high incidence of cigarette smoking among individuals with schizophrenia [85]. This study complements the human postmortem epigenetic data and supports epigenetic modification as a potentially reversible mechanism of GAD67 deficiency. However, coincidence of GAD67 rescue with symptomatic improvement in the short and long term remains unclear [84, 86]. Importantly, neither haloperidol nor olanzapine reduced GABA-associated gene expression in nonhuman primates ruling out medication effects as a primary cause of GAD67 reduction in the human postmortem brain of subjects with schizophrenia [33]. Interneuron deficits have also emerged as principle components of other animal models of schizophrenia. For example, one of the most studied animal models is the neonatal ventral hippocampal lesion (NVHL) rat model [87–89]. Excitotoxic lesion of the ventral hippocampus 1 week following birth (P7–P8) leads to adolescent onset of changes in dopaminergic systems, cortical circuitry, and behavior associated with schizophrenia [87, 90]. GABA system dysfunction is a core component of the NVHL model with multiple research groups reporting decreased GAD67 [91] and increased GABA A receptor [92, 93] gene expression as well as decreased interneuron cell number in some regions [94]. One of the main findings in the NVHL model is altered dopaminergic regulation of prefrontal circuits. O’Donnell et al. [95] found that stimulating the ventral tegmental area increased prefrontal cortex pyramidal cell firing in lesioned animals while decreasing firing in sham-treated rats which may be the result of dysfunctional ventral tegmental area inputs onto prefrontal cortex interneurons. Later work showing a loss of D2 receptor modulation of prefrontal cortex interneurons in NVHL rats supports this interpretation [96]. At the behavioral level, psychosis cannot be readily ascertained in model animals since hallucinations and delusions are not quantifiable traits. In contrast, neurobiology underlying motivation, reward, social behavior, decisionmaking, affective behavior, and learning and memory is remarkably similar in rodents, nonhuman primates, and humans [97–101]. Human studies report that amygdalocortical and corticolimbic circuit disturbances in schizophrenia are likely related to altered motivation and decision-making [102, 103], and that basolateral amygdala interactions with orbitofrontal cortices (which dynamically encode the value of stimuli [97, 104–107]) are necessary for adaptive learning and cognition [108–110]. All these disturbances can be assessed and modeled in mice, but at 4

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a detail and time course that far exceeds the resolution limits of human studies. Importantly, the negative and cognitive symptoms related to schizophrenia are relatively well-suited for modeling, and their consideration represents a tremendous clinical need since they are consistent predictors of prognosis and are not well managed with current medications [111, 112]. In fact, many schizophrenia-related behavioral processes have been extensively investigated in rodents [110, 113–115], shedding light on the underlying molecular mechanisms. For example, such studies revealed that dopamine regulates interneuron activity in the amygdala and basolateral amygdala afferents increase connections with interneurons in the prefrontal cortex during development. Therefore, it is possible that the dopamine and GABA systems act synergistically to regulate decision-making, reward, social and goal-directed behavior, suggesting that the GABAergic deficits contribute to the emergence of behavioral impairments seen in schizophrenic patients [63, 99, 116–129]. Arriving at these types of knowledge using human subject-based research is not feasible, clearly arguing that deciphering the pathophysiology of schizophrenia will require integration of human and animal model data sets. When considering the utility of modeling complex psychiatric disorders in animals, it is important to define the goal of the research and the context of the analyses. Recapitulating schizophrenia in an animal model is an unrealistic goal. However, we can use animal models to discover fundamental molecular and genetic processes that drive behavior. Furthermore, we can perturb the critical molecular-cellular systems, and understand their contribution to various behavioral domains, which in fact might be critical for understanding the symptoms of various disorders. Since the negative and cognitive behavioral domains are much more translatable between patients and rodent models and they represent a tremendous need for therapeutic development, it seems appropriate to promote the analysis of animal models in these areas. Furthermore, if it is determined that GAD67 expression in particular cell types regulates specific domains of behavior, therapeutic strategies that target various interneuron cell types should be promising avenues for a knowledgebased approach to the treatment of schizophrenia.

Conclusions

We conclude that GABA system dysfunction in schizophrenia is a common, well-reproduced, multicausal and physiologically relevant finding, and might be one of the Schmidt/Mirnics

final common pathways of the disease pathophysiology. Since dopaminergic and glutamatergic system perturbations lead to GAD67 downregulation and changes in interneuron development, it is possible that GABAergic dysfunction is a critical component of all existing theories of schizophrenia. While creating a ‘schizophrenic mouse’ is impossible, understanding the contribution of specific interneuron cell types to behavior will be essential for deciphering the role GAD67 deficiency plays in

the pathophysiology and symptomatology of schizophrenia. Once we understand the functional impact of these deficits, we can develop knowledge-based therapeutic targets for the treatment of this devastating disease; just as Kraepelin suggested nearly a century ago: ‘However little it may be possible to identify human with animal brain-functions and illnesses, yet, from the effects produced by particular noxae in the brains of animals, conclusions can be drawn as to the issue of like processes in man’ [9].

References 1 Kessler RC, et al: The prevalence and correlates of nonaffective psychosis in the National Comorbidity Survey Replication (NCS-R). Biol Psychiatry 2005; 58:668–676. 2 Lewis DA, Levitt P: Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 2002;25:409–432. 3 Weinberger DR: Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44:660–669. 4 Crown WH, et al: Hospitalization and total medical costs for privately insured persons with schizophrenia. Adm Policy Ment Health 2001;28:335–351. 5 Hennekens CH, et al: Schizophrenia and increased risks of cardiovascular disease. Am Heart J 2005;150:1115–1121. 6 Saha S, Chant D, McGrath J: A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry 2007;64:1123–1131. 7 Masand PS, et al: Metabolic and endocrine disturbances in psychiatric disorders: a multidisciplinary approach to appropriate atypical antipsychotic utilization. CNS Spectr 2005;10(suppl 14):1–15. 8 World Health Organization: The Global Burden of Disease: 2004 Update. Geneva, World Health Organization, 2008. 9 Kraepelin E: Ziele und Wege der psychiatrischen Forschung. Arbeiten aus der Deutschen Forschungsanstalt für Psychiatrie in München (Ends and Means of Psychiatric Research; 1922 transl). J Ment Sci 1919; 68:115–143. 10 Zilboorg G: Eugen Bleuler and present-day psychiatry. Am J Psychiatry 1957; 114: 289– 298. 11 Watson JB: Psychology as the behaviorist views it. Psychol Rev 1913;20:158–177. 12 Arnold SE, et al: Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998;55:225–232. 13 Van Kammen DP: ␥-Aminobutyric acid (GABA) and the dopamine hypothesis of schizophrenia. Am J Psychiatry 1977; 134: 138–143.

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14 Roberts E: Prospects for research on schizophrenia. An hypothesis suggesting that there is a defect in the GABA system in schizophrenia. Neurosci Res Program Bull 1972; 10:468–482. 15 Spokes EG, et al: Distribution of GABA in post-mortem brain tissue from control, psychotic and Huntington’s chorea subjects. J Neurol Sci 1980;48:303–313. 16 Hanada S, et al: [3H]muscimol binding sites increased in autopsied brains of chronic schizophrenics. Life Sci 1987;40:259–266. 17 Benes FM, et al: Increased GABA A receptor binding in superficial layers of cingulate cortex in schizophrenics. J Neurosci 1992; 12: 924–929. 18 Hashimoto T, et al: Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 2008;13:147–161. 19 Simpson MD, et al: Reduced GABA uptake sites in the temporal lobe in schizophrenia. Neurosci Lett 1989;107:211–215. 20 Benes FM, et al: Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 1991;48:996–1001. 21 Daviss SR, Lewis DA: Local circuit neurons of the prefrontal cortex in schizophrenia: selective increase in the density of calbindinimmunoreactive neurons. Psychiatry Res 1995;59:81–96. 22 Wang AY, et al: Bipolar disorder type 1 and schizophrenia are accompanied by decreased density of parvalbumin- and somatostatin-positive interneurons in the parahippocampal region. Acta Neuropathol 2011;122:615–626. 23 Akbarian S, 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. 24 Martin DL, Rimvall K: Regulation of gamma-aminobutyric acid synthesis in the brain. J Neurochem 1993;60:395–407. 25 Lewis DA, Hashimoto T, Volk DW: Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005;6:312–324.

Dev Neurosci

26 Knable MB, et al: Molecular abnormalities in the major psychiatric illnesses: Classification and Regression Tree (CRT) analysis of post-mortem prefrontal markers. Mol Psychiatry 2002;7:392–404. 27 Akbarian S, Huang HS: Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Res Rev 2006;52:293–304. 28 Costa E, et al: A GABAergic cortical deficit dominates schizophrenia pathophysiology. Crit Rev Neurobiol 2004;16:1–23. 29 Kalkman HO, Loetscher E: GAD(67): the link between the GABA-deficit hypothesis and the dopaminergic- and glutamatergic theories of psychosis. J Neural Transm 2003; 110:803–812. 30 Mirnics K, et al: Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 2000;28:53–67. 31 Fatemi SH, et al: GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum. Schizophr Res 2005; 72: 109–122. 32 Hashimoto T, 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. 33 Hashimoto T, et al: Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry 2008;13:147–161. 34 Hashimoto T, et al: Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. Am J Psychiatry 2008; 165: 479–489. 35 Guidotti A, 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. 36 Straub RE, et al: Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. Mol Psychiatry 2007;12:854–869.

5

37 Du J, et al: Comprehensive analysis of polymorphisms throughout GAD1 gene: a family-based association study in schizophrenia. J Neural Transm 2008;115:513–519. 38 Addington AM, et al: GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol Psychiatry 2005;10:581–588. 39 Veldic M, et al: DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proc Natl Acad Sci USA 2004;101:348–353. 40 Huang HS, Akbarian S: GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia. PLoS One 2007;2:e809. 41 Ruzicka WB, et al: Selective epigenetic alteration of layer I GABAergic neurons isolated from prefrontal cortex of schizophrenia patients using laser-assisted microdissection. Mol Psychiatry 2007;12:385–397. 42 Veldic M, et al: Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder. Schizophr Res 2007;91:51–61. 43 Veldic M, et al: In psychosis, cortical interneurons overexpress DNA-methyltransferase 1. Proc Natl Acad Sci USA 2005; 102: 2152–2157. 44 Benes FM: Regulation of cell cycle and DNA repair in post-mitotic GABA neurons in psychotic disorders. Neuropharmacology 2011; 60:1232–1242. 45 Hyde TM, et al: Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia. J Neurosci 2011;31:11088–11095. 46 Ikeda K, et al: Distribution of neuropeptide Y interneurons in the dorsal prefrontal cortex of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 379– 383. 47 Ascoli GA, et al: Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat Rev Neurosci 2008;9:557–568. 48 Kawaguchi Y, Aosaki T, Kubota Y: Cholinergic and GABAergic interneurons in the striatum. Nihon Shinkei Seishin Yakurigaku Zasshi 1997;17:87–90. 49 Kubota Y, et al: Selective coexpression of multiple chemical markers defines discrete populations of neocortical GABAergic neurons. Cereb Cortex 2011;21:1803–1817. 50 Tepper JM, Bolam JP: Functional diversity and specificity of neostriatal interneurons. Curr Opin Neurobiol 2004;14:685–692. 51 Sosulina L, Graebenitz S, Pape HC: GABAergic interneurons in the mouse lateral amygdala: a classification study. J Neurophysiol 2010;104:617–626. 52 Markram H, et al: Interneurons of the neocortical inhibitory system. Nat Rev Neurosci 2004;5:793–807.

6

Dev Neurosci

53 Woodruff AR, Sah P: Networks of parvalbumin-positive interneurons in the basolateral amygdala. J Neurosci 2007;27:553–563. 54 Woodruff AR, Anderson SA, Yuste R: The enigmatic function of chandelier cells. Front Neurosci 2010;4:201. 55 Meziane H, et al: Distribution of cholecystokinin immunoreactivity in the BALB/c mouse forebrain: an immunocytochemical study. J Chem Neuroanat 1997;12:191–209. 56 Hornung JP, De Tribolet N, Tork I: Morphology and distribution of neuropeptide-containing neurons in human cerebral cortex. Neuroscience 1992;51:363–375. 57 Geola FL, et al: Regional distribution of cholecystokinin-like immunoreactivity in the human brain. J Clin Endocrinol Metab 1981; 53:270–275. 58 Foldy C, et al: Cell type-specific gating of perisomatic inhibition by cholecystokinin. Nat Neurosci 2007;10:1128–1130. 59 Freund TF: Interneuron diversity series: rhythm and mood in perisomatic inhibition. Trends Neurosci 2003;26:489–495. 60 Olah S, et al: Regulation of cortical microcircuits by unitary GABA-mediated volume transmission. Nature 2009;461:1278–1281. 61 Karagiannis A, et al: Classification of NPYexpressing neocortical interneurons. J Neurosci 2009;29:3642–3659. 62 Partridge JG, et al: Excitatory and inhibitory synapses in neuropeptide Y-expressing striatal interneurons. J Neurophysiol 2009; 102: 3038–3045. 63 Truitt WA, et al: Anxiety-like behavior is modulated by a discrete subpopulation of interneurons in the basolateral amygdala. Neuroscience 2009;160:284–294. 64 Garbett KA, 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. 65 Jones EG: The origins of cortical interneurons: mouse versus monkey and human. Cereb Cortex 2009;19:1953–1956. 66 Letinic K, Zoncu R, Rakic P: Origin of GABAergic neurons in the human neocortex. Nature 2002;417:645–649. 67 Metin C, et al: Modes and mishaps of neuronal migration in the mammalian brain. J Neurosci 2008;28:11746–11752. 68 Flames N, et al: Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcriptional codes. J Neurosci 2007;27:9682–9695. 69 Long JE, et al: Dlx1&2 and Mash1 transcription factors control MGE and CGE patterning and differentiation through parallel and overlapping pathways. Cereb Cortex 2009; 19(suppl 1):96–106. 70 Crandall JE, et al: Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex. J Neurosci 2007;27:3813–3822.

71 Galve-Roperh I, et al: The endocannabinoid system and the regulation of neural development: potential implications in psychiatric disorders. Eur Arch Psychiatry Clin Neurosci 2009;259:371–382. 72 Harrison PJ, Weinberger DR: Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005;10:40–68;image 5. 73 Neddens J, et al: Conserved interneuronspecific ErbB4 expression in frontal cortex of rodents, monkeys, and humans: implications for schizophrenia. Biol Psychiatry 2011; 70:636–645. 74 Marenco S, et al: Genetic association of ErbB4 and human cortical GABA levels in vivo. J Neurosci 2011;31:11628–11632. 75 Eastwood SL, Harrison PJ: Interstitial white matter neuron density in the dorsolateral prefrontal cortex and parahippocampal gyrus in schizophrenia. Schizophr Res 2005;79: 181–188. 76 Connor CM, Guo Y, Akbarian S: Cingulate white matter neurons in schizophrenia and bipolar disorder. Biol Psychiatry 2009; 66: 486–493. 77 Lindefors N: Dopaminergic regulation of glutamic acid decarboxylase mRNA expression and GABA release in the striatum: a review. Prog Neuropsychopharmacol Biol Psychiatry 1993;17:887–903. 78 Laprade N, Soghomonian JJ: Differential regulation of mRNA levels encoding for the two isoforms of glutamate decarboxylase (GAD65 and GAD67) by dopamine receptors in the rat striatum. Brain Res Mol Brain Res 1995;34:65–74. 79 Qin ZH, Zhang SP, Weiss B: Dopaminergic and glutamatergic blocking drugs differentially regulate glutamic acid decarboxylase mRNA in mouse brain. Brain Res Mol Brain Res 1994;21:293–302. 80 Sato M, Numachi Y, Hamamura T: Relapse of paranoid psychotic state in methamphetamine model of schizophrenia. Schizophr Bull 1992;18:115–122. 81 Javitt DC, Zukin SR: Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry 1991;148:1301–1308. 82 Krystal JH, et al: Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199– 214. 83 Guidotti A, et al: Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling. Trends Pharmacol Sci 2009;30:55–60. 84 Guidotti A, et al: Epigenetic GABAergic targets in schizophrenia and bipolar disorder. Neuropharmacology 2011; 60:1007–1016. 85 Satta R, et al: Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons. Proc Natl Acad Sci USA 2008;105:16356–16361.

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86 Thomsen MS, et al: ␣(7) Nicotinic acetylcholine receptor activation prevents behavioral and molecular changes induced by repeated phencyclidine treatment. Neuropharmacology 2009;56:1001–1009. 87 O’Donnell P: Cortical disinhibition in the neonatal ventral hippocampal lesion model of schizophrenia: new vistas on possible therapeutic approaches. Pharmacol Ther 2012;133:19–25. 88 Tseng KY, Chambers RA, Lipska BK: The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia. Behav Brain Res 2009; 204: 295–305. 89 Lipska BK, Weinberger DR: A neurodevelopmental model of schizophrenia: neonatal disconnection of the hippocampus. Neurotox Res 2002;4:469–475. 90 Lipska BK, Jaskiw GE, Weinberger DR: Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology 1993; 9:67–75. 91 Lipska BK, et al: Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs. Eur J Neurosci 2003;18:391–402. 92 Mitchell CP, Grayson DR, Goldman MB: Neonatal lesions of the ventral hippocampal formation alter GABA-A receptor subunit mRNA expression in adult rat frontal pole. Biol Psychiatry 2005; 57:49–55. 93 Endo K, et al: Alterations in GABA(A) receptor expression in neonatal ventral hippocampal lesioned rats: comparison of prepubertal and postpubertal periods. Synapse 2007;61:357–366. 94 Francois J, et al: Selective reorganization of GABAergic transmission in neonatal ventral hippocampal-lesioned rats. Int J Neuropsychopharmacol 2009;12:1097–1110. 95 O’Donnell P, et al: Neonatal hippocampal damage alters electrophysiological properties of prefrontal cortical neurons in adult rats. Cereb Cortex 2002;12:975–982. 96 Tseng KY, et al: A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. J Neurosci 2008;28:12691–12699. 97 Morrison SE, Salzman CD: Re-valuing the amygdala. Curr Opin Neurobiol 2010; 20: 221–230. 98 Bissonette GB, et al: Double dissociation of the effects of medial and orbital prefrontal cortical lesions on attentional and affective shifts in mice. J Neurosci 2008; 28: 11124– 11130. 99 Schultz W: Potential vulnerabilities of neuronal reward, risk, and decision mechanisms to addictive drugs. Neuron 2011;69:603–617.

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100 Robbins TW: Chemical neuromodulation of frontal-executive functions in humans and other animals. Exp Brain Res 2000;133: 130–138. 101 Seymour B, Dolan R: Emotion, decision making, and the amygdala. Neuron 2008; 58:662–671. 102 Benes FM: Amygdalocortical circuitry in schizophrenia: from circuits to molecules. Neuropsychopharmacology 2009; 35: 239– 257. 103 Waltz JA, et al: Abnormal responses to monetary outcomes in cortex, but not in the basal ganglia, in schizophrenia. Neuropsychopharmacology 2010;35:2427–2439. 104 Murray EA, Wise SP: Interactions between orbital prefrontal cortex and amygdala: advanced cognition, learned responses and instinctive behaviors. Curr Opin Neurobiol 2010;20:212–220. 105 Gallagher M, McMahan RW, Schoenbaum G: Orbitofrontal cortex and representation of incentive value in associative learning. J Neurosci 1999;19:6610–6614. 106 Schoenbaum G, et al: Encoding predicted outcome and acquired value in orbitofrontal cortex during cue sampling depends upon input from basolateral amygdala. Neuron 2003;39:855–867. 107 Saddoris MP, Gallagher M, Schoenbaum G: Rapid associative encoding in basolateral amygdala depends on connections with orbitofrontal cortex. Neuron 2005; 46: 321– 331. 108 Kehagia AA, Murray GK, Robbins TW: Learning and cognitive flexibility: frontostriatal function and monoaminergic modulation. Curr Opin Neurobiol 2010;20:199– 204. 109 Gruber AJ, et al: More is less: a disinhibited prefrontal cortex impairs cognitive flexibility. J Neurosci 2010;30:17102–17110. 110 Schoenbaum G, Esber GR: How do you (estimate you will) like them apples? Integration as a defining trait of orbitofrontal function. Curr Opin Neurobiol 2010; 20: 205–211. 111 Green MF: What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996; 153: 321–330. 112 Kirkpatrick B, et al: The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 2006;32:214–219. 113 Cardinal RN, et al: Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobehav Rev 2002;26:321–352. 114 Donaldson ZR, Young LJ: Oxytocin, vasopressin, and the neurogenetics of sociality. Science 2008;322:900–904. 115 Dalley JW, Cardinal RN, Robbins TW: Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 2004; 28: 771–784.

Dev Neurosci

116 Marowsky A, et al: A specialized subclass of interneurons mediates dopaminergic facilitation of amygdala function. Neuron 2005; 48:1025–1037. 117 Lisman JE, et al: Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia. Trends Neurosci 2008;31:234–242. 118 Diaz MR, et al: Dopamine D3-like receptors modulate anxiety-like behavior and regulate GABAergic transmission in the rat lateral/basolateral amygdala. Neuropsychopharmacology 2011;36:1090–1103. 119 Zweifel LS, et al: Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety. Nat Neurosci 2011;14:620–626. 120 de Oliveira AR, et al: Conditioned fear is modulated by D(2) receptor pathway connecting the ventral tegmental area and basolateral amygdala. Neurobiol Learn Mem 2011;95:37–45. 121 Boulougouris V, Dalley JW, Robbins TW: Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat. Behav Brain Res 2007;179:219–228. 122 Gendreau PL, et al: D2-like dopamine receptor mediation of social-emotional reactivity in a mouse model of anxiety: strain and experience effects. Neuropsychopharmacology 1998;18:210–221. 123 Wall PM, et al: Infralimbic D2 receptor influences on anxiety-like behavior and active memory/attention in CD-1 mice. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:395–410. 124 Truitt WA, et al: From anxiety to autism: spectrum of abnormal social behaviors modeled by progressive disruption of inhibitory neuronal function in the basolateral amygdala in Wistar rats. Psychopharmacology (Berl) 2007;191:107–118. 125 Likhtik E, et al: Amygdala intercalated neurons are required for expression of fear extinction. Nature 2008;454:642–645. 126 de la Mora MP, et al: Role of dopamine receptor mechanisms in the amygdaloid modulation of fear and anxiety: structural and functional analysis. Prog Neurobiol 2010;90:198–216. 127 Takahashi YK, et al: Expectancy-related changes in firing of dopamine neurons depend on orbitofrontal cortex. Nat Neurosci 2011;14:1590–1597. 128 Cunningham MG, Bhattacharyya S, Benes FM: Increasing interaction of amygdalar afferents with GABAergic interneurons between birth and adulthood. Cereb Cortex 2008;18:1529–1535. 129 Leeson VC, et al: Discrimination learning, reversal, and set-shifting in first-episode schizophrenia: stability over six years and specific associations with medication type and disorganization syndrome. Biol Psychiatry 2009;66:586–593.

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