Schizophrenia is a complex disorder with diverse positive and negative symptoms. Although positive symptoms are the most overt and dramatic manifestations of the disorder, the negative symptoms are the most persistent and crippling. Intense efforts over the last two decades have established that cognitive deficits are core features of schizophrenia. These cognitive deficits are related to pervasive negative symptoms and are a major source of disability, but current antipsychotic treatments do little to improve these memory deficits. The research in this project focuses on investigating the fundamental cognitive deficits associated with schizophrenia, modeling this basic 'endophenotype'in laboratory animals. We will examine disturbances in declarative memory using genetic, pharmacological and biochemical approaches. Other projects in the Center are focused on the response of neural circuits to novelty and deviant sensory stimuli using imaging and electrophysiological approaches in an effort to investigate the idea that altered stimulus encoding might underlie schizophrenia. Ultimately, these altered neuronal responses translate into alterations in behavior. In this project, we extend this focus on responses to novelty to the behavioral level, examining the molecular mechanisms of memory storage for a visual paired comparison task in rodents, termed novel object recognition, in which we measure the extent to which mice prefer novel objects. Importantly, variants of these tasks have been studied in rodents, primates and humans, revealing that this task depends on the medial temporal lobe memory system. Further, patients exhibit deficits in such tasks. Recent evidence suggests that disturbances in intracellular signaling may contribute to schizophrenia. Studies in humans indicate that activity within the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway may be altered in the central nervous systems of schizophrenia patients. Our own studies indicate that transgenic mice overexpressing a constitutively active form of the signaling protein Gsa in forebrain neurons, exhibit several endophenotypes of schizophrenia that can be reversed by treatment with antipsychotics. Using a novel object recognition task, this project will examine the effects of altered cAMP/PKA signaling using genetic (Specific Aim 1) and pharmacological approaches (Specific Aim 2) on memory in mice to determine whether altered intracellular signaling contributes to this endophenotype of schizophrenia. In addition, recent genetic and neuropathological studies implicate dysbindin in schizophrenia, and we will examine the behavioral effects of dysbindin mutations in mice (Specific Aim 3). These behavioral genetic studies promise to expand our knowledge of the molecular mechanisms of memory, storage, enabling us to develop better treatments for this aspect of the cognitive impairments in schizophrenia.
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