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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH064045-10
Application #
8118816
Study Section
Special Emphasis Panel (ZMH1)
Project Start
2010-08-01
Project End
2011-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
10
Fiscal Year
2010
Total Cost
$242,484
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
van Erp, Theo G M; Walton, Esther; Hibar, Derrek P et al. (2018) Cortical Brain Abnormalities in 4474 Individuals With Schizophrenia and 5098 Control Subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium. Biol Psychiatry 84:644-654
Walton, E; Hibar, D P; van Erp, T G M et al. (2017) Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium. Acta Psychiatr Scand 135:439-447
Barz, Claudia S; Bessaih, Thomas; Abel, Ted et al. (2016) Sensory encoding in Neuregulin 1 mutants. Brain Struct Funct 221:1067-81
Satterthwaite, Theodore D; Wolf, Daniel H; Calkins, Monica E et al. (2016) Structural Brain Abnormalities in Youth With Psychosis Spectrum Symptoms. JAMA Psychiatry 73:515-24
Welle, Cristin G; Contreras, Diego (2016) Sensory-driven and spontaneous gamma oscillations engage distinct cortical circuitry. J Neurophysiol 115:1821-35
Satterthwaite, Theodore D; Connolly, John J; Ruparel, Kosha et al. (2016) The Philadelphia Neurodevelopmental Cohort: A publicly available resource for the study of normal and abnormal brain development in youth. Neuroimage 124:1115-9
Barz, Claudia S; Bessaih, Thomas; Abel, Ted et al. (2016) Altered resonance properties of somatosensory responses in mice deficient for the schizophrenia risk gene Neuregulin 1. Brain Struct Funct 221:4383-4398
Collier, Azurii K; Wolf, Daniel H; Valdez, Jeffrey N et al. (2014) Subsequent memory effects in schizophrenia. Psychiatry Res 224:211-7
Müller, Veronika I; Kellermann, Tanja S; Seligman, Sarah C et al. (2014) Modulation of affective face processing deficits in Schizophrenia by congruent emotional sounds. Soc Cogn Affect Neurosci 9:436-44
Glen Jr, W Bailey; Horowitz, Bryant; Carlson, Gregory C et al. (2014) Dysbindin-1 loss compromises NMDAR-dependent synaptic plasticity and contextual fear conditioning. Hippocampus 24:204-13

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