A core element of schizophrenia is the presence of persistant, debilitating cognitive impairments. The cognitiveabilities most affected working memory, selective attention, and cognitive flexibility are called executive functions because they organize goal-oriented behaviors across time. They require the coordinated activity of multiple brain regionsthat have as a common node the prefrontal cortex (PFC). Executive-function deficits are considered to pose the mostimportant barrier to a schizophrenic person s recovery and reintegration into society. Unfortunately, they are poorlytreated by current antipsychotics. The development of effective treatments has been slowed by the fact that there is as yetno clear understanding, at the cellular or systems level, of the causal neural bases of this complex disorder. Recent studies suggest that abnormally decreased inhibitory signaling by neurons releasing gamma-aminobutyric acid(GABA), in particular within the PFC, may cause abberant neural circuit activity, resulting in the impaired cognitionassociated with schizophrenia. GABA activity is crucial in shaping the excitability and patterned activity of glutamatergicprincipal neurons; abberant GABA signalling would thus dysregulate activity of both local neural circuits and brain-widenetworks. If this hypothesis is accurate, then drugs that increase GABA tone may restore or improve cognitive function. The overarching goal of the proposed research project is to test the hypothesis that diminished GABAergic signalingis a fundamental factor contributing to schizophrenia-associated cognitive deficits. Two complementary, yet independent,approaches will be used. The first approach will evaluate the cognitive effects of GABA system modulators injecteddirectly into the rat prefrontal cortex. Drugs that act at GABA modulatory sites, including allosteric sites on GABAAreceptors, cannabinoid CB1 receptors, and GABA transporters, will be tested for their effects on tasks that measureworking memory, recognition memory, and cognitive flexibility, and, in particular, for their abilities to block or attenutatecognitive impairments induced by administering the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonistMK-801. Low-dose NMDA antagonist administration induces a widely used preclinical model of schizophrenia; it isthought to impair cognition by interfering with GABA function. If schizophrenia-like cognitive impairments are causedby reduced GABA signaling, then drugs that augment GABA signaling should block or attenuate the cognitive deficits.Conversely, drugs that act on GABA signaling to further decrease inhibitory activity should exacerbate the effects of MK-801. The second approach will identify the neural networks activated by performing tasks that measure executive functionand will characterize how network activity is altered by MK-801, alone and in combination with GABA modulators.Network activity will be identified by quantifying regional behavior-dependent changes in levels of the protein productsof two immediate early genes, Fos and Arc. Fos expression indicates general behavior-dependent neural activation; Arcexpression marks regions of synaptic plasticity and information storage. These experiments will provide useful evidencefor or against GABA dysfunction as a causal mechanism of schizophrenia-associated cognitive deficits and will furnishdeep understanding of the neural bases of executive cognitive functions in a widely used rat model of schizophrenia.
The cognitive problems associated with schizophrenia; which include impaired memory; attention; and flexibility ofthought; are considered to be the major obstacle affecting treatment outcome and quality of life. Unfortunately; cognitiveimpairments are not adequately treated by current antipsychotic medications. The proposed experiments; by testing thehypothesis that schizophrenia-associated cognitive impairments are due to reduced neural inhibition; and identifying brainregions associated with cognitive functions using a rat model of the disorder; will help determine the causal mechanismsof schizophrenia-associated cognitive impairments and will greatly aid in the development of new treatments.
