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Dev Neurosci 2012;34:152–158 DOI: 10.1159/000336731

Modeling Interneuron Dysfunction in Schizophrenia

Martin J. Schmidt Karoly Mirnics

Department of Psychiatry, Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tenn. , USA

cinations and delusions, negative symptoms including social withdrawal, anhedonia, and avolition among oth-ers, and cognitive symptoms including deficits in work-ing memory, disorganized thought, and attention. The cause(s) of schizophrenia remain(s) elusive although ge-netic and environmental disruptions in neurodevel-opment remain a consistent focus [2, 3] . Patients typi-cally 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, includ-ing 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 unipo-lar depression and alcohol abuse [8] . The financial and personal toll of the illness reaches from patient to popula-tion and working towards a better understanding of its development will enable more effective treatments that alleviate that strain.

Two people who have influenced schizophrenia re-search 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/

Key Words

Schizophrenia � Gene expression � GAD67 � Interneurons � 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 ex-pression of the gene encoding the 67-kDa isoform of glutam-ic 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 defi-cits in schizophrenia encompass multiple interneuronal sub-types, 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 physiol-ogy? Finally, will this knowledge open the door to knowledge-based approaches to treat schizophrenia?

Copyright © 2012 S. Karger AG, Basel

Introduction

Schizophrenia is a debilitating disorder affecting ap-proximately 1% of the population [1] . Its symptoms fall into three domains: positive symptoms including hallu-

Published online: May 8, 2012

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

© 2012 S. Karger AG, Basel0378–5866/12/0343–0152$38.00/0

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Dev Neurosci 2012;34:152–158 153

or pathology that might explain its symptoms [9] . In con-trast, Eugen Bleuler described it as schizophrenia, or ‘split mind’, and believed connecting with patients individu-ally was more beneficial to understanding the illness than studying neurobiology [10] . Psychosis, the defining fea-ture of schizophrenia, is impairment in distinguishing reality amongst hallucinations and delusions. This pre-sents a problem for researchers interested in mental ill-ness. Is it possible to quantify reality and study its neuro-biology 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, psycho-logical 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 incor-porate those complicated ‘internal’ processes that have quantifiable outcomes such as value judgments, motiva-tion, and decision-making, which are now also thought to be dysfunctional in schizophrenia. No causal pathology exists for schizophrenia [12] . However, alterations in neu-ral 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 mod-els. 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 re-ceptor 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 tis-sue and found a decrease in the 67-kDa isoform of glu-tamic acid decarboxylase (GAD67) mRNA in the pre-frontal cortex that cell loss could not account for. GAD67

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 differ-ent brain regions, patient cohorts, methods, and investi-gators, 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 sug-gesting a role in regulating gene expression and not pro-tein function. An analysis of patients with a GAD1 ge-netic variant suggested that DNA sequence variation can effectively regulate mRNA expression levels in the post-mortem tissue of subjects with schizophrenia [36] . A sec-ond mechanism that may contribute to decreased GAD67 expression in schizophrenia is epigenetics. Genes can be suppressed when promoters or other regulatory sequenc-es are methylated causing changes in chromatin struc-ture that prevent transcription [39] . Methylation is car-ried out by enzymes such as DNMT1 which is overex-pressed in GABAergic interneurons of schizophrenic patients and correlated with decreased GAD67 mRNA in the same cells suggesting dysfunctional epigenetic regu-lation of the gene; however, a causal relationship between increased DNMT1 and GAD1 promoter methylation has not been established conclusively in postmortem stud-ies [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 develop-ment via changes in cell cycle regulation [44] , impair-ments in interneuron maturation [45] , and migration de-fects [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 altera-tions 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,

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and is this related to altered behavior? Second, do differ-ent 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 cel-lular, molecular, and behavioral processes and have pro-vided insight into potential mechanisms of GABA system dysfunction in human disorders.

GABAergic cell types are so diverse that creating a no-menclature 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 inter-neurons 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 chole-cystokinin (CCK) are molecular markers of distinct inter-neuron populations [49] . PV-positive chandelier cells syn-apse on the axon initial segments and basket cells regulate the cell soma of pyramidal cells, regulating output and in-tegration across multiple cortical and subcortical areas [52–54] . In contrast, CCK-positive basket cells regulate in-hibition of pyramidal cell soma directly via synaptic trans-mission and indirectly via modulation of other interneu-rons primarily in limbic and frontal circuits [55–59] . Furthermore, neuropeptide-Y-positive neurogliaform and Martinotti interneurons release GABA via volume trans-mission [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 exam-ple, PV-positive chandelier cells appear to control � -oscil-lations 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 inter-neuronal contribution to behavioral processes, our labora-tory has recently developed several novel mouse models that downregulate GAD67 in specific classes of interneu-rons [64] . Using a synthetic miRNA, GAD67 was down-regulated in CCK-positive, neuropeptide-Y-positive, PV-positive and CNR1-positive interneurons using BAC-driv-

en, fluorescent constructs. In the targeted cell populations of the transgenic animals, GAD67 expression was abol-ished by 70–95%, but without a seizure phenotype. Pre-liminary data indicate that the tested interneuronal cell types regulate different, well-defined physiological and behavioral processes. Therefore, we argue that future ther-apeutic interventions directed toward restoring the func-tion of specific interneuronal cell types might be a promis-ing approach to developing conceptually novel, knowl-edge-based therapies of schizophrenia, geared toward alleviating the most debilitating symptoms of the disease.

There are two important caveats that must be ac-knowledged when comparing the development of GABA-ergic circuitry in human and mouse. First, the propor-tion of interneurons to pyramidal cells in the human cortex is much greater than in the mouse [65] . This dis-crepancy also raises the possibility that interneuron def-icits in human could have more robust effects on behavior than what is seen in the transgenic rodent models. Sec-ond, up to 65% of human cortical interneurons arise from an alternate source of progenitors in the neocortical ven-tricular and subventricular zone that may have developed during primate evolution [66] . Regardless of these cave-ats, rodent models to assess the differentiation and mi-gration of GABAergic interneurons from the ganglionic eminences [67–69] are very informative about the neuro-biological processes underlying the developmental as-pects of schizophrenia. For example, dopamine [70] , can-nabinoids [71] and multiple schizophrenia susceptibility genes [72, 73] play roles in regulating interneuron migra-tion and synapse formation during development in mice and may contribute to GABA system developmental dis-turbances in schizophrenia [46, 74–76] .

Complementing the genetic population-based studies and expression/epigenetic data from postmortem re-search, 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 D 2 recep-tor stimulation [77, 78] or acute NMDA receptor antago-nism [79] in multiple brain regions. These data mirror the ability of chronic dopamine stimulation [80] and acute NMDA receptor antagonism [81, 82] to precipitate psycho-sis in humans. Thus, the NMDA hypofunction hypothe-sis, the dopamine hypothesis, and the GABA dysfunction hypothesis of schizophrenia could be integrated with GAD67 deficiency being a player in each [29] . Further-more, 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, demethyl-ated the GAD1 promoter, and increased GAD67 protein levels which may explain in part the high incidence of cig-arette smoking among individuals with schizophrenia [85] . This study complements the human postmortem epi-genetic data and supports epigenetic modification as a po-tentially reversible mechanism of GAD67 deficiency. However, coincidence of GAD67 rescue with symptom-atic improvement in the short and long term remains un-clear [84, 86] . Importantly, neither haloperidol nor olan-zapine reduced GABA-associated gene expression in non-human primates ruling out medication effects as a pri-mary 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 hippo-campus 1 week following birth (P7–P8) leads to adoles-cent 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 find-ings in the NVHL model is altered dopaminergic regula-tion of prefrontal circuits. O’Donnell et al. [95] found that stimulating the ventral tegmental area increased prefron-tal 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 D 2 receptor modulation of prefrontal cortex interneu-rons in NVHL rats supports this interpretation [96] .

At the behavioral level, psychosis cannot be readily as-certained in model animals since hallucinations and delu-sions are not quantifiable traits. In contrast, neurobiology underlying motivation, reward, social behavior, decision-making, affective behavior, and learning and memory is remarkably similar in rodents, nonhuman primates, and humans [97–101] . Human studies report that amygdalo-cortical and corticolimbic circuit disturbances in schizo-phrenia are likely related to altered motivation and deci-sion-making [102, 103] , and that basolateral amygdala in-teractions 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

a detail and time course that far exceeds the resolution limits of human studies. Importantly, the negative and cognitive symptoms related to schizophrenia are relative-ly well-suited for modeling, and their consideration rep-resents a tremendous clinical need since they are consis-tent predictors of prognosis and are not well managed with current medications [111, 112] . In fact, many schizo-phrenia-related behavioral processes have been extensive-ly investigated in rodents [110, 113–115] , shedding light on the underlying molecular mechanisms. For example, such studies revealed that dopamine regulates interneuron ac-tivity 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-direct-ed behavior, suggesting that the GABAergic deficits con-tribute to the emergence of behavioral impairments seen in schizophrenic patients [63, 99, 116–129] . Arriving at these types of knowledge using human subject-based re-search 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 crit-ical molecular-cellular systems, and understand their contribution to various behavioral domains, which in fact might be critical for understanding the symptoms of var-ious disorders. Since the negative and cognitive behav-ioral domains are much more translatable between pa-tients 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. Fur-thermore, if it is determined that GAD67 expression in particular cell types regulates specific domains of behav-ior, therapeutic strategies that target various interneuron cell types should be promising avenues for a knowledge-based approach to the treatment of schizophrenia.

Conclusions

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

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

the pathophysiology and symptomatology of schizophre-nia. 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 par-ticular noxae in the brains of animals, conclusions can be drawn as to the issue of like processes in man’ [9] .

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