Schizophrenia is a severe and chronic brain disorder that affects ∼1% of the population. Although psychotic symptoms, such as delusions and hallucinations, are usually the presenting and most striking clinical feature of the illness, disturbances in certain crucial cognitive functions, such as working memory, are now considered to represent core features of the illness. The degree of cognitive impairment is the best predictor of long-term functional outcome in individuals with schizophrenia, but, at present, no effective treatments for these symptoms are available. Therefore, the development of new therapeutics requires increased knowledge of the underlying disease process.
Working memory deficits in schizophrenia reflect dysfunction of the dorsolateral prefrontal cortex (DLPFC), and convergent lines of evidence indicate that this dysfunction is due, at least in part, to disturbances in a subpopulation of GABA (γ-aminobutyric acid) interneurons. For example, the expression of the mRNAs for the 67 kiloDalton isoform of glutamic acid decarboxylase (GAD67), an enzyme responsible for the synthesis of GABA, and for the GABA membrane transporter (GAT1) are decreased in the parvalbumin-expressing subpopulation of prefrontal GABA neurons. These changes in the parvalbumin-containing chandelier class of GABA neurons are associated with a marked post-synaptic upregulation of GABAA (GABA type A) receptors containing an α2 subunit in the axon initial segment of pyramidal cells, the synaptic target of chandelier neuron axon terminals. Convergent findings in both postmortem human brain specimens and genetically engineered mice indicate that deficient neurotrophin signalling through the tyrosine kinase Trk (tropomyosin-related kinase) receptor B (TrkB) might be a pathogenetic mechanism that underlies the reduced gene expression and impaired inhibitory neurotransmission in chandelier neurons.
It is proposed that the deficient inhibitory output from parvalbumin-expressing GABA neurons might impair the synchronization of DLPFC activity in the gamma-frequency oscillations that accompany normal working memory function. Consequently, pharmacological agents that selectively increase phasic GABA mediated function at the chandelier neuron inputs to pyramidal cell axon initial segments might improve working memory function in individuals with schizophrenia.
Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (γ-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
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Work by the authors cited in this manuscript was supported by grants from the National Institutes of Health and by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (T.H.). The authors thank M. Brady and L. Konopka for excellent assistance with the figures and text.
D.A.L. receives investigator-initiated research support from Lilly, Pfizer and Merck, and serves as a consultant for Pfizer.
This refers to distortions in inferential thinking, such as delusions (fixed, false beliefs that are firmly held in the face of contradictory evidence), and perceptual disturbances, such as hallucinations. Auditory hallucinations, usually experienced as voices distinct from one's own thoughts, are most common in schizophrenia.
- WORKING MEMORY
The active maintenance of limited amounts of information for a short period of time to guide thought processes or sequences of behaviour. Working memory is typically assessed through delayed response tasks in which a stimulus cue is briefly presented and removed, a delay period ensues, and then a response is required based on information contained in the stimulus cue.
- DORSOLATERAL PREFRONTAL CORTEX
(DLPFC). Those regions on the dorsal surface of the primate frontal lobe that are located rostral to the motor and premotor regions, and which include Brodmann's areas 9 and 46.
- PYRAMIDAL NEURONS
These constitute ∼75% of cortical neurons, and are recognized by their triangular cell bodies, a single apical dendrite directed toward the cortical surface and an array of basilar dendrites. The dendrites of these neurons are studded with many spines, and their axons project into the white matter and provide excitatory projections to other cortical regions or subcortical structures.
- GABA NEURONS
These comprise ∼25% of cortical neurons, have smooth or sparsely spiny dendrites and provide axons that project locally within the cortical grey matter.
Reelin is a large protein that is secreted into the extracellular matrix by Cajal–Retzius cells. It regulates the migration of cortical neurons during development. The absence of reelin in the reeler mouse results in a distinctive alteration of the normal cellular architecture of the cortex.
Benzodiazepines bind to GABAA receptors, where they increase the frequency of opening of Cl− channels in the presence of GABA, but do not directly open channels in the absence of GABA. At present, the available benzodiazepines are not selective for GABAA receptors that contain the α2 subunit, and so produce a range of effects, such as the sedation mediated by the α1 subunit, which can impair cognitive processes.
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Lewis, D., Hashimoto, T. & Volk, D. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6, 312–324 (2005). https://doi.org/10.1038/nrn1648
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