cAMP/PKA Signaling and Endophenotypes of Schizophrenia

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

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