Until recently an analysis of the pathogenic mechanisms of schizophrenia has been impeded by a difficulty in identifying genetic clear mutations. In the Scottish family, a balanced (1:11) (q42.1;q14.3) translocation co-segregates with major psychiatric disorders. On chromosome 1, the translocation breakpoint disrupts the gene, named Disrupted In Schizophrenia 1 (DISC1) that has been recognized as a strong candidate gene for major psychiatric illness. Prior studies with the CAMKII promoter-driven inducible expression of mutant DISC1 have demonstrated that expression of mutant DISC1 in pyramidal neurons leads schizophrenia-like neurobehavioral alterations, including a reduction in the numbers of parvalbumin-positive (PV+) neurons in the cortex and hippocampus, consistent with the neuropathology of schizophrenia. However, the mechanisms of enhanced vulnerability of PV+ neurons remain poorly understood. We propose to generate and characterize a mouse model with selective perturbations of DISC1 signaling in PV+ neurons to further mechanistic investigations of their pathology and resultant cognitive dysfunctions in schizophrenia.
Specific Aim 1 will characterize the basic features of inducible expression of mutant DISC1 driven by the Pvalb-2A promoter and regulated by the Tet-off system. We will determine the time course of expression of mutant DISC1 and regulation of expression by DOX and we will identify what brain regions and cell types express mutant DISC1 in mice.
Specific Aim 2 will identify the effects of mutant DISC1 on schizophrenia-like behaviors and pathology of PV+ neurons. We will evaluate sensorimotor gating, working memory and social behavior in adult control and mutant DISC1 mice. We will also perform a stereology-based analysis of numbers of PV+ neurons in the cortex of control and mutant DISC1 mice.
Specific Aim 3 will identify the effects of mutant DISC1 on functional properties of PV+ interneurons of the frontal cortex. We will evaluate the electrical properties of PV+ neurons of the frontal cortex. The experiment will provide important insights into altered functions of PV+ neurons and will identify the neurophysiologic correlates of the abnormal behaviors in DISC1 mice. We believe that this research training application not only will generate a mouse model to promote molecular studies of the parvalbumin pathology but also will provide the unmatched opportunity for training of the candidate to advance his future research career in Russia and become a leader in the newly developing field of translational neuroscience.
The research training fellowship application proposes to generate a novel mouse model to study the molecular mechanisms whereby a genetic risk factor, Disrupted-In-Schizophrenia 1 (DISC1), associated with schizophrenia, affects development and functioning of cortical neurons, parvalbumin-positive cells, which are impaired in schizophrenia. The proposal not only will generate a mouse model to promote future molecular studies in the pathogenesis of the key pathology of schizophrenia but also will provide the unmatched opportunity for superb training of the candidate as well as advance his future research career in Russia to become a leader in newly developing translational neuroscience.
|Shevelkin, Alexey V; Ihenatu, Chinezimuzo; Pletnikov, Mikhail V (2014) Pre-clinical models of neurodevelopmental disorders: focus on the cerebellum. Rev Neurosci 25:177-94|