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

Impairments 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 gamma-aminobutyric acid and excitatory glutamate neurotransmission in the dorsolateral prefrontal cortex. Specifically, reduced gamma-aminobutyric acid synthesis is present in the subpopulation of gamma-aminobutyric acid neurons that express the calcium-binding protein parvalbumin. Despite presynaptic and postsynaptic compensatory responses, the resulting impaired inhibitory regulation of pyramidal 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 secondary 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 cognitive function in individuals with schizophrenia.

[1]  Philip D. Harvey,et al.  Impact of neuroleptic medications on continuous performance test measures in schizophrenia , 1996, Biological Psychiatry.

[2]  A. Malhotra,et al.  Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. , 1999, The American journal of psychiatry.

[3]  Marc W Howard,et al.  Gamma oscillations correlate with working memory load in humans. , 2003, Cerebral cortex.

[4]  G. Elston,et al.  The human temporal cortex: characterization of neurons expressing nitric oxide synthase, neuropeptides and calcium-binding proteins, and their glutamate receptor subunit profiles. , 2001, Cerebral cortex.

[5]  Andrew C. Leon,et al.  A Placebo-Controlled Pilot Study of the Ampakine CX516 Added to Clozapine in Schizophrenia , 2001, Journal of clinical psychopharmacology.

[6]  David A Lewis,et al.  Catching Up on Schizophrenia Natural History and Neurobiology , 2000, Neuron.

[7]  R. Gur,et al.  Working memory deficit as a core neuropsychological dysfunction in schizophrenia. , 2003, The American journal of psychiatry.

[8]  A. Sampson,et al.  Gene Expression Deficits in a Subclass of GABA Neurons in the Prefrontal Cortex of Subjects with Schizophrenia , 2003, The Journal of Neuroscience.

[9]  J. Coyle.  The GABA-glutamate connection in schizophrenia: which is the proximate cause? , 2004, Biochemical pharmacology.

[10]  Stephan Heckers,et al.  Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. , 2003, Pharmacology & therapeutics.

[11]  T. Goldberg,et al.  Cognitive impairment in schizophrenia is the core of the disorder. , 2000, Critical reviews in neurobiology.

[12]  B. Moghaddam,et al.  Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release , 2004, Neuropsychopharmacology.

[13]  D. Lewis,et al.  Cortical inhibitory neurons and schizophrenia , 2005, Nature Reviews Neuroscience.

[14]  J. Morrison,et al.  Quantitative localization of NMDAR1 receptor subunit immunoreactivity in inferotemporal and prefrontal association cortices of monkey and human , 1997, Brain Research.

[15]  J. Coyle,et al.  The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia , 2004, Psychopharmacology.

[16]  T. Woo,et al.  A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Miles A Whittington,et al.  Interneuron Diversity series: Inhibitory interneurons and network oscillations in vitro , 2003, Trends in Neurosciences.

[18]  David A Lewis,et al.  Schizophrenia as a disorder of neurodevelopment. , 2002, Annual review of neuroscience.

[19]  Zin Z. Khaing,et al.  Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs , 2003, The European journal of neuroscience.

[20]  A. Sampson,et al.  GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. , 2001, The American journal of psychiatry.

[21]  J. Lieberman,et al.  The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. , 1999, Schizophrenia bulletin.

[22]  B. Moghaddam,et al.  NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[23]  M C O'Donovan,et al.  The molecular genetics of schizophrenia: new findings promise new insights , 2004, Molecular Psychiatry.

[24]  B. Morris,et al.  Induction of Metabolic Hypofunction and Neurochemical Deficits after Chronic Intermittent Exposure to Phencyclidine: Differential Modulation by Antipsychotic Drugs , 2003, Neuropsychopharmacology.

[25]  M. Egan,et al.  Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series , 2002, Schizophrenia Research.

[26]  B. Moghaddam,et al.  Bursting of prefrontal cortex neurons in awake rats is regulated by metabotropic glutamate 5 (mGlu5) receptors: rate-dependent influence and interaction with NMDA receptors. , 2006, Cerebral cortex.

[27]  P. Goldman-Rakic,et al.  Destruction and Creation of Spatial Tuning by Disinhibition: GABAA Blockade of Prefrontal Cortical Neurons Engaged by Working Memory , 2000, The Journal of Neuroscience.

[28]  A. Sampson,et al.  Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. , 2000, Archives of general psychiatry.

[29]  J. Cohen,et al.  Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. , 2001, The American journal of psychiatry.

[30]  A. Sampson,et al.  Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. , 2002, Cerebral cortex.

[31]  Bita Moghaddam,et al.  Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia , 2004, Psychopharmacology.

[32]  Paul J. Harrison,et al.  Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence , 2005, Molecular Psychiatry.

[33]  J. Gold.  Cognitive deficits as treatment targets in schizophrenia , 2004, Schizophrenia Research.

[34]  Jonathan D. Cohen,et al.  Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in never-medicated patients with first-episode psychosis. , 2005, American Journal of Psychiatry.

[35]  T. Freund,et al.  Total Number and Ratio of Excitatory and Inhibitory Synapses Converging onto Single Interneurons of Different Types in the CA1 Area of the Rat Hippocampus , 1999, The Journal of Neuroscience.

[36]  David A Lewis,et al.  Pyramidal neuron local axon terminals in monkey prefrontal cortex: differential targeting of subclasses of GABA neurons. , 2003, Cerebral cortex.

[37]  Bita Moghaddam,et al.  Bringing Order to the Glutamate Chaos in Schizophrenia , 2003, Neuron.

[38]  E. G. Jones,et al.  Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. , 1995, Archives of general psychiatry.

[39]  M. Egan,et al.  Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. , 2003, The American journal of psychiatry.

[40]  J. Krystal,et al.  Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. , 1994, Archives of general psychiatry.