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Cognitive Dysfunction in Schizophrenia Convergence of ␥-Aminobutyric Acid and Glutamate Alterations

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Cognitive Dysfunction in Schizophrenia Convergence of ␥-Aminobutyric Acid and Glutamate Alterations NEUROLOGICAL REVIEW Cognitive Dysfunction in Schizophrenia Convergence of ␥-Aminobutyric Acid and Glutamate Alterations David A. Lewis, MD; Bita Moghaddam, PhD mpairments in certain cognitive functions mediated by the dorsolateral prefrontal cortex, such as working memory, are core features of schizophrenia. Convergent findings suggest that these disturbances are associated with alterations in markers of inhibitory ␥-amino- butyric acid and excitatory glutamate neurotransmission in the dorsolateral prefrontal cor- Itex. Specifically, reduced ␥-aminobutyric acid synthesis is present in the subpopulation of ␥-ami- nobutyric acid neurons that express the calcium-binding protein parvalbumin. Despite presynaptic and postsynaptic compensatory responses, the resulting impaired inhibitory regulation of pyra- midal neurons contributes to a reduction in the synchronized neuronal activity that is required for working memory function. Several lines of evidence suggest that these changes may be either sec- ondary to or exacerbated by impaired signaling via the N-methyl-D-aspartate class of glutamate receptors. These findings suggest specific targets for therapeutic interventions to improve cogni- tive function in individuals with schizophrenia. Arch Neurol. 2006;63:1372-1376 Schizophrenia typically has its clinical on- sist throughout the illness, (2) exist in set during late adolescence or early adult- milder forms in the unaffected relatives of hood and is frequently associated with a individuals with schizophrenia, and (3) are lifetime of disability.1 A number of puta- the best predictor of long-term functional tive susceptibility genes for schizophre- outcome.5 Consequently, the develop- nia have been identified recently,2 al- ment of therapeutic interventions for these though the risk of illness associated with cognitive deficits is a major focus of re- any particular genetic variant seems small. search in schizophrenia. In addition, a range of adverse environ- Certain cognitive deficits in schizo- mental events, occurring from concep- phrenia reflect alterations in processes, tion through adolescence, seems to in- such as working memory, that are medi- crease the likelihood of developing ated by the circuitry of the dorsolateral pre- schizophrenia later in life.3 Thus, schizo- frontal cortex (DLPFC). Many individu- phrenia is thought to arise from altered als with schizophrenia perform poorly on neurodevelopmental trajectories because working memory tasks and exhibit al- of the interaction of genetic susceptibil- tered activation of the DLPFC when at- ity and environmental risk factors. tempting to perform such tasks.6 In con- Although psychosis is usually the most trast, these abnormalities are not present striking clinical aspect of schizophrenia, dis- in individuals with other psychotic disor- turbances in certain cognitive processes, ders.7 The altered activation of the DLPFC such as attention, certain types of memory, during working memory tasks predicts the and executive functions, are considered to severity of cognitive disorganization in be the core features of the illness.4 Such cog- subjects with schizophrenia,8 and re- nitive disturbances (1) can be present for duced working memory capacity may be years before the onset of psychosis and per- a key factor in the performance of other cognitive tasks in those with schizophre- Author Affiliations: Departments of Psychiatry and Neuroscience, University of nia.9 Because working memory deficits Pittsburgh, Pittsburgh, Pa. seem to be a central feature of schizophre- (REPRINTED) ARCH NEUROL / VOL 63, OCT 2006 WWW.ARCHNEUROL.COM 1372 ©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 nia, determining the nature of the underlying distur- of subjects with schizophrenia express decreased levels bances in DLPFC circuitry is essential for the identifica- of PV mRNA and undetectable levels of GAD67 and GAT1 tion of new drug targets. mRNAs, with the latter resulting in reduced GAT1 pro- Although other neurotransmitter systems are cer- tein in the axon cartridges of these neurons. In addi- tainly involved, findings from a number of investigations tion, the density of pyramidal neuron axon initial seg- ␥ ␣ suggest that disturbances in inhibitory -aminobutyric acid ments immunoreactive for the GABA type A (GABAA) 2 (GABA)–mediated10 or excitatory glutamate-medi- subunit is markedly increased in schizophrenia,19 appar- 11,12 ␣ ated neurotransmission may contribute to the cogni- ently reflecting higher levels of 2 subunits in the axon tive impairments of schizophrenia. In this article, we briefly initial segment. These changes are not found in subjects review this evidence, consider the potential relationships with other psychiatric disorders or in monkeys exposed that may exist between the GABA and glutamate abnor- long term to antipsychotic medications, suggesting that malities, and discuss the implications of these findings for they are specific to the disease process of schizophre- pharmacological interventions to improve cognitive per- nia.15-17,19 Thus, in the DLPFC of subjects with schizo- formance in individuals with schizophrenia. phrenia, GABAA receptors are up-regulated at pyrami- dal neuron axon initial segments in response to deficient ALTERED GABA NEUROTRANSMISSION GABA release from chandelier neuron axon terminals.10 AND COGNITIVE DISTURBANCES Understanding the contribution of these abnormali- IN SCHIZOPHRENIA ties to the cognitive deficits in schizophrenia depends on the demonstration of a pathophysiological process by Working memory depends on the coordinated and sus- which reduced chandelier cell inputs to pyramidal neu- tained firing of subsets of DLPFC pyramidal neurons be- rons could give rise to working memory impairments. tween the temporary presentation of the stimulus cue and Networks of PVϩ fast-spiking GABA neurons, formed the later initiation of the behavioral response, and fast- by chemical and electrical synapses, give rise to oscilla- spiking GABA neurons in the DLPFC seem essential for tory activity in the ␥-band range, the synchronized fir- such synchronization of pyramidal neuron activity.13 These ing of a population of neurons at 30 to 80 Hz.20 Inter- findings suggest that impairments in GABA-mediated in- estingly, ␥-band oscillations in the DLPFC increase in hibition in the DLPFC could contribute to the impair- proportion to working memory load,21 and in subjects ments in working memory present in schizophrenia. Con- with schizophrenia, DLPFC ␥-band oscillations are re- sistent with this interpretation, reduced expression of the duced during the delay period of a working memory task.22 messenger RNA (mRNA) for the 67-kDa isoform of glu- Thus, a deficit in the synchronization of pyramidal cells, ϩ tamic acid decarboxylase (GAD67), an enzyme that syn- resulting from impaired inhibition by PV GABA neu- thesizes GABA, is one of the most consistent findings in rons, might contribute to reduced ␥-band oscillations and, postmortem studies10 of individuals with schizophrenia. consequently, to working memory dysfunction in sub- 10 The mRNA expression of GAD67 is undetectable in a sub- jects with schizophrenia. population (about 25%-30%) of DLPFC GABA neu- rons,14,15 whereas most GABA neurons have normal lev- GLUTAMATE NEUROTRANSMISSION 15 els of GAD67 mRNA. Furthermore, in the same AND COGNITIVE DISTURBANCES individuals, the mRNA expression for the GABA mem- IN SCHIZOPHRENIA brane transporter (GAT1), a protein responsible for the reuptake of released GABA into nerve terminals, is simi- Glutamate mediates fast excitatory postsynaptic poten- larly decreased in a subpopulation of GABA neurons.16 tials by acting on the ionotropic receptors: ␣-amino-3- Thus, the synthesis and reuptake of GABA are reduced in hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), a subset of DLPFC inhibitory neurons in schizophrenia. N-methyl-D-aspartate (NMDA), and kainate. Glutamate The affected GABA neurons include those that con- also exerts modulatory effects by acting on different sub- tain the calcium-binding protein parvalbumin (PV), which types of G protein–coupled metabotropic glutamate is present in approximately 25% of GABA neurons in the (mGlu) receptors. For example, the group 5 mGlu re- primate DLPFC, whereas the approximately 50% of GABA ceptors (mGlu5) potentiate the duration of NMDA re- neurons that express the calcium-binding protein cal- ceptor–dependent excitatory postsynaptic potentials, retinin (CR) are unaffected.17 The PV-positive (PVϩ) neu- whereas mGlu2 and mGlu3 receptors modulate the re- rons are also distinguishable from other cortical GABA lease of glutamate.12 The glutamate synapse is also in- neurons by their fast-spiking, nonadapting, firing pat- fluenced by efficient excitatory amino acid transport pro- tern, and subsets of these neurons can be identified by teins on glial cells and by a host of molecules that influence their morphological features.10 For example, the axons glutamate receptor trafficking and the intracellular sig- of the chandelier subclass of PVϩ GABA neurons give naling machinery associated with postsynaptic density. rise to linear arrays of terminals (termed cartridges) that The following lines of evidence implicate these glu- synapse exclusively on the axon initial segments of py- tamate receptors and glutamate receptor–associated ramidal neurons. In the DLPFC of subjects with schizo- molecules in the pathophysiological features of schizo- phrenia, the density of chandelier
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