Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

doi:10.1016/j.tins.2008.02.005

Trends in Neurosciences

Volume 31, Issue 5, May 2008, Pages 234-242

https://doi.org/10.1016/j.tins.2008.02.005 Get rights and content

Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

Introduction

Schizophrenia affects nearly 1% of the population [1]. Clinically, the disorder is characterized by positive symptoms (psychosis, hallucinations and paranoia), negative symptoms (flat affect, poor attention, lack of motivation and deficits in social function) and cognitive deficits. Population, family and twin studies indicate that schizophrenia is highly heritable, but no single gene has a strong effect. Rather, the disorder is due to the synergistic interaction of multiple genes and environmental factors [2]. Recent association and linkage studies have identified over a dozen risk genes for schizophrenia [3]. Another line of research has focused on neurotransmitter systems and, again, the evidence, rather than identifying a single factor, points to abnormalities in multiple systems: glutamate, GABA, dopamine and acetylcholine have all been implicated. There is therefore a strong need for an integrative approach to explain how multiple genes and neurotransmitters can interact in a synergistic way to produce the disorder. In this review, we will describe neural circuitry that provides a framework for understanding many of these interactions. Our description builds on several previous integrative approaches 4, 5 but extends that work in several ways, notably by suggesting a systems-level explanation for the changes in GABAergic interneurons that occur in schizophrenia.

Section snippets

GABA hypofunction

Studies of postmortem brain tissue have provided strong evidence that the GABAergic system is impaired in schizophrenia (this is termed hypofunction). These studies showed reductions in the concentration of cortical GABA [6] and the activity of glutamate decarboxylase (GAD) [7], the enzyme that synthesizes GABA. These observations were confirmed and extended in subsequent studies showing alteration in several presynaptic components of the GABAergic system 8, 9, 10, 11, 12, 13, 14. The GABA

NMDA hypofunction

The NMDA hypofunction theory of schizophrenia (reduced NMDA channel function) is based on two findings: (i) dissociative anesthetics (PCP, MK801 and ketamine) are antagonists of NMDA receptors, and (ii) when abused, these drugs induce a condition that resembles schizophrenia [28]. In laboratory experiments, a subanesthetic dose of ketamine given to normal volunteers induces the symptoms of schizophrenia more effectively than any other known drug 29, 30, 31, 32. NMDA antagonists reproduce both

NMDA/GABA interaction: disinhibition

In pyramidal cells, excitatory postsynaptic potential (EPSPs) are generated primarily by AMPA channels; the main role of NMDA channels in these cells is in the synaptic plasticity that underlies learning. It was therefore unclear why administration of NMDA antagonist to humans should have large effects on mental processes not related to learning. A key finding [53] was the discovery that NMDA channels contribute strongly to the EPSP in interneurons and that acute inhibition of these channels

NMDARs on interneurons as a sensor for homeostatic regulation of pyramidal cell firing

The existence of an NMDAR-mediated component of the EPSP in interneurons helps to connect the NMDA and GABA hypotheses, but does not explain the decreased expression of GAD and parvalbumin. Here we propose a novel explanation of this decrease. Our starting point is the idea that a major function of the fast-spiking interneurons is the homeostatic regulation of overall pyramidal cell firing. These interneurons sum the responses from hundreds of pyramidal cells and then inhibit these cells, thus

The hyperdopaminergic state and the role of the hippocampus

Dopamine was the first neurotransmitter system to be strongly implicated in schizophrenia. Antagonists of the D2 receptor reduce the positive symptoms of the disorder 85, 86, and standard drug treatments of schizophrenia remain based on this antagonism. By implication, it would seem that the disease might be due to a hyperdopaminergic state (excess dopamine). Consistent with this, increasing dopamine release with amphetamine produces positive symptoms in normal subjects [87]. Direct evidence

Disinhibition might produce some cognitive symptoms by reducing gamma oscillations

In the above section, we explored how malfunction of the feedback loop between pyramidal cells and fast-spiking interneurons could affect the dopamine system. In addition, this loop is directly involved in the generation of gamma oscillations and there are now strong reasons for believing that abnormalities in these oscillations could contribute to some of the symptoms of schizophrenia. Gamma frequency (30–100 Hz) oscillations are present in the local field potential and EEG, reflecting the

The cholinergic system: reversing disinhibition and cognitive deficits

The disinhibition model described above is also useful in understanding the role of the cholinergic system in schizophrenia [118]. One hint of the relevance of the cholinergic system to schizophrenia is that the prevalence of smoking among individuals with schizophrenia exceeds 70%, 2- to 4-fold higher than in the general population [119]. This heavy use of nicotine is believed to be an attempt at self-medication [120]. In controlled experiments on schizophrenia patients, nicotine has been

Toward a circuit-based explanation of synergistic gene action

The goal of systems biology is to understand how genes work together in biochemical and cellular networks to produce function. Such an integrated understanding is of special importance in schizophrenia research because the disorder results from the synergistic interaction of many risk genes, none of which has a large effect. To determine whether genes act synergistically, it is necessary to have a circuit-based model. This is illustrated by analysis of NMDAR function; these receptors are

Acknowledgements

The authors would like to thank Gordon Fain for advice on the manuscript and Margarita Behrens and Claudia Racca for useful discussions. J.E.L., J.T.C., D.C.J. and R.W.G. are grateful for the support of NIH Conte Center grant P50 MH060450. F.M.B. has been supported by NIH grants MH42261, MH31862 and MH60450. S.H. has been supported by MH067999 and MH070560. R.W.G. gratefully acknowledges support from the Department of Veterans Affairs.

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The primary inhibitory neurotransmitter γ-aminobutyric acid (GABA) has a prominent role in regulating neural development and function, with disruption to GABAergic signalling linked to behavioural phenotypes associated with neurodevelopmental disorders, particularly autism. Such neurochemical disruption, likely resulting from diverse genetic and molecular mechanisms, particularly during early development, can subsequently affect the cellular balance of excitation and inhibition in neuronal circuits, which may account for the social processing difficulties observed in autism and related conditions. This comprehensive narrative review integrates diverse streams of research from several disciplines, including molecular neurobiology, genetics, epigenetics, and systems neuroscience. In so doing it aims to elucidate the relevance of inhibitory dysfunction to autism, with specific focus on social processing difficulties that represent a core feature of this disorder. Many of the social processing difficulties experienced in autism have been linked to higher levels of the excitatory neurotransmitter glutamate and/or lower levels of inhibitory GABA. While current therapeutic options for social difficulties in autism are largely limited to behavioural interventions, this review highlights the psychopharmacological studies that explore the utility of GABA modulation in alleviating such difficulties.
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Dysfunction of glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia and may be particularly relevant in severe, treatment-resistant symptoms. The underlying mechanism may involve hypofunction of the NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed of genetic variants within NMDA receptor encoding genes, are associated with cortical glutamate in schizophrenia. Anterior cingulate cortex (ACC) glutamate was measured in 70 participants across 4 research sites using Proton Magnetic Resonance Spectroscopy (¹H-MRS). Two NMDA receptor gene sets were sourced from the Molecular Signatories Database and NMDA receptor pathway polygenic scores were constructed using PRSet. The NMDA receptor pathway polygenic scores were weighted by single nucleotide polymorphism (SNP) associations with treatment-resistant schizophrenia, and associations with ACC glutamate were tested. We then tested whether NMDA receptor pathway polygenic scores with SNPs weighted by associations with non-treatment-resistant schizophrenia were associated with ACC glutamate. A higher NMDA receptor complex pathway polygenic score was significantly associated with lower ACC glutamate (β = −0.25, 95 % CI = −0.49, −0.02, competitive p = 0.03). When SNPs were weighted by associations with non-treatment-resistant schizophrenia, there was no association between the NMDA receptor complex pathway polygenic score and ACC glutamate (β = 0.05, 95 % CI = −0.18, 0.27, competitive p = 0.79). These results provide initial evidence of an association between common genetic variation implicated in NMDA receptor function and ACC glutamate levels in schizophrenia. This association was specific to when the NMDA receptor complex pathway polygenic score was weighted by SNP associations with treatment-resistant schizophrenia.
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Abnormal neurotransmitter levels have been reported in individuals at high risk for schizophrenia, leading to a shift in the excitatory/inhibitory balance. However, it is unclear whether these alterations predate the onset of clinically relevant symptoms. Our aim was to explore in vivo measures of excitatory/inhibitory balance in 22q11.2 deletion carriers, a population at genetic risk for psychosis.
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These findings demonstrate that GluN2D in PVIs serves as a point of convergence of pathways involved in the regulation of GABAergic synapses relevant to SZ.

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Trends in Neurosciences

OpinionCircuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Introduction

Section snippets

GABA hypofunction

NMDA hypofunction

NMDA/GABA interaction: disinhibition

NMDARs on interneurons as a sensor for homeostatic regulation of pyramidal cell firing

The hyperdopaminergic state and the role of the hippocampus

Disinhibition might produce some cognitive symptoms by reducing gamma oscillations

The cholinergic system: reversing disinhibition and cognitive deficits

Toward a circuit-based explanation of synergistic gene action

Acknowledgements

Lancet

Neurosci. Lett.

Schizophr. Res.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Neuroscience

Neuropsychopharmacology

Cell

Biol. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

Neurosci. Lett.

Neuron

Trends Neurosci.

J. Psychiatr. Res.

Biol. Psychiatry

Epilepsy Behav.

Neuroscience

Trends Neurosci.

Neuroscience

J. Psychiatr. Res.

Neuron

Schizophr. Res.

Schizophr. Res.

Lifetime prevalence of psychotic and bipolar I disorders in a general population

Arch. Gen. Psychiatry

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

Mol. Psychiatry

Finding schizophrenia genes

J. Clin. Invest.

Cognitive dysfunction in schizophrenia: convergence of γ-aminobutyric acid and glutamate alterations

Arch. Neurol.

The neurochemical circuitry of schizophrenia

Pharmacopsychiatry

Computed tomographic brain studies and treatment response in schizophrenia

Can. J. Psychiatry

Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics

Arch. Gen. Psychiatry

Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study

Arch. Gen. Psychiatry

Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical γ-aminobutyric acid neurons in subjects with schizophrenia

Arch. Gen. Psychiatry

Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia

Arch. Gen. Psychiatry

Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder

Arch. Gen. Psychiatry

GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons

Am. J. Psychiatry

Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients

Arch. Gen. Psychiatry

A subclass of prefrontal γ-aminobutyric acid axon terminals are selectively altered in schizophrenia

Proc. Natl. Acad. Sci. U. S. A.

Schizophrenia and the parvalbumin-containing class of cortical local circuit neurons

Am. J. Psychiatry

Cortical inhibitory neurons and schizophrenia

Nat. Rev. Neurosci.

Regional survey of GABA-related gene expression in the neocortex of subjects with schizophrenia

Schizophr. Bull.

Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars

Proc. Natl. Acad. Sci. U. S. A.

Differences in the subregional and cellular distribution of GABAA receptor binding in the hippocampal formation of schizophrenic brain

Synapse

Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia

Cereb. Cortex

Cingulate cortex GABA concentration in schizophrenia: a two-dimensional proton magnetic resonance spectroscopy study

Biol. Psychiatry

Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation

Arch. Gen. Psychiatry

Opinion
Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Differences in the subregional and cellular distribution of GABA_A receptor binding in the hippocampal formation of schizophrenic brain