Schizophrenia is characterized by abnormalities in perception, working memory, attention and learning. The pathogenesis of the disease involves a combination of genetic and environmental factors that affect regulation and expression of genes governing brain function. The convergence of genetic and external factors results in abnormalities in brain development and maturation that involve distributed neural circuits and neurotransmitter systems.Cognitive deficits in schizophrenia may be partially due to an inability to interpret complex sensory inputs that leads to the dramatic manifestations of the disease such as confusion, sensory illusions and delusions of reference. A basic premise of this Center is that the inability to interpret complex multimodal sensory stimuli starts with abnormalities in early detection and encoding of stimulus characteristics. Here we will study basic elements of early information encoding as expressed by their electrophysiological signatures. We will attempt to correlate specific electrophysiological markers, such as amplitude and spatiotemporal distribution of sensory driven activity in neocortex, with specific alterations of glutamatergic transmission and cAMP metabolism that may represent endophenotypes of schizophrenia. The experiments proposed here will be conducted under anesthesia, but the two mouse models used in this proposal, as well as the injection of ketamine in wild type mouse, will be validated as endophenotypes in the awake behaving condition in subproject 0008. In addition, the parallel with the human abnormalities will be established by closely following, in the mouse, the electrophysiological protocols and analysis used in humans in subprojects 0001 and 0002. The focus of this proposal is on establishing a basic set of parameters or measures to which different endophenotypes of sensory encoding deficits can be compared. We believe that by understanding how specific changes in circuitry and neurotrasmission alter responsiveness in cortex we may gain a handle on the basic pathophysiological processes of schizophrenia. This project will quantify, in the mouse, the spatiotemporal distribution of somatosensory evoked potentials and their associated evoked gamma oscillations (aim 1). We will study the effect of theta frequency input on gamma oscillations (aim 1). We will compare the responses of the wild type mouse with those obtained after specific neurotransmitter alterations such as in the dysbindin mutant mouse """"""""Sandy"""""""", the Gsa transgenic mouse and wild type mouse after injection of the NMDA blocker ketamine (aim 2). We will explore the cellular and network mechanisms underlying abnormal rhythm generation in slices of neocortex in vitro, obtained from mice previously recorded in vivo (aim 3).

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1)
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University of Pennsylvania
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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
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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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