Cellular /Network Mechanisms Abnormalities in Stimulus Encoding in Mouse Models

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications & trials

Abstract

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