Cognitive Dysfunction in Schizophrenia
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| A Novel, Pathophysiology-Based Treatment Intervention for Cognitive Dysfunction in Schizophrenia |
| Critical cognitive deficits in schizophrenia, such as impairments in working memory, are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). Postmortem investigations indicate that these cognitive deficits might reflect alterations in the expression of certain genes in specific populations of GABA, neurons in the DLPFC (Figure 1). In particular, the synthesis of GABA is reduced in the chandelier class of GABA neurons that furnish inputs exclusively to the axon initial segment of excitatory pyramidal neurons. This deficit in GABA neurotransmission is associated with an up-regulation of GABAA receptors that contain alpha-2 subunits, which are preferentially localized to pyramidal neuron axon initial segments. Since chandelier neurons appear to play a critical role in regulating the synchronization of pyramidal neuron firing during working memory, these findings suggest that the alterations in chandelier neurons in schizophrenia represent a pathological entity that gives rise to the pathophysiology of altered neuronal synchronization and the clinical feature of impaired working memory. Parallel studies in genetically-engineered mice support this conclusion. |
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| Figure 1. Schematic summary of alterations in GABA circuitry in the dorsolateral
prefrontal cortex of individuals with schizophrenia. Reduced levels of
gene expression in chandelier neurons (blue) are associated with a decrease
in immunoreactivity (IR) for GABA (?-aminobutyric acid) transporter 1
(GAT1) in the axon cartridges of these neurons and an upregulation of
GABAA receptor a2 subunit immunoreactivity in the postsynaptic axon initial
segment of pyramidal neurons (green). Gene expression in the calretinin
(CR)-expressing subpopulation of GABA neurons (yellow) does not seem to
be altered. GAD67, 67 kD isoform of glutamic acid decarboxylase; PV, parvalbumin;
1-6, layers of dorsolateral prefrontal cortex. (Lewis DA, Hashimoto T,
Volk DW: Cortical inhibitory neurons and schizophrenia. Nature Reviews
Neuroscience 6:312-324, 2005.) |
| Together, these findings suggest that a medication which enhances GABAergic neurotransmission only at pyramidal neuron axon initial segments and which preserves the normal timing of chandelier neuron activity could improve working memory function. In order to test this hypothesis, we have identified a novel drug with these properties and have implemented a proof-of-concept clinical trial to determine whether the short-term administration of this investigational drug provides evidence of improvement in neuronal synchronization in the prefrontal cortex and in cognitive functioning. Male volunteers with a diagnosis of schizophrenia or schizoaffective disorder and on stable doses of an atypical antipsychotic medication are randomly assigned to the study medication or placebo in a double-blind fashion. |