Nellie E. Byun, Ph.D. - US grants

DESCRIPTION (provided by applicant): Our laboratory has generated K+-Cl-contransporter-3 (KCC3) knockout mice, which exhibit severe locomotor deficits. This phenotype mirrors the peripheral neuropathy in patients with mutations in the human KCC3 gene who suffer from a neurological disorder termed Andermann syndrome, or ACCPN. Both show myelination abnormalities in peripheral nerves, e.g. hypomyelination, demyelination, and fiber degeneration. Although KCC3 is undetectable in sciatic nerve of mice postnatal 20 days and older, preliminary immunostaining results show that KCC3 is highly expressed in Schwann cell (SC) bodies during early development, which corresponds to the period of SC migration, proliferation, and myelination. Thus we hypothesize that KCC3 lays a critical role in one or more of these processes. Functional SCs are crucial since proper myelination is necessary for normal action potential conduction. The goal of this proposal is to define the role of KCC3 in SC development. Although its physiological role is unknown, KCC3 mediates the electroneutral movement of K+ and Cl- ions, can regulate cell volume, and is associated with cell proliferation. We will first determine the exact localization and expression pattern of KCC3 in peripheral nerves. Then to test our hypothesis, we will compare motility, myelination ability, and proliferation and apoptosis levels between wild type and KCC3-/-SCs in order to understand cotransporter function in SCs. This study will also reveal new information on peripheral nerve development.

DESCRIPTION (provided by applicant): The overall goals of this proposal are to quantitatively characterize the effects on neural activation and cerebral networks of novel compounds that target metabotropic glutamate receptor subype 2 (mGlu2) using functional neuroimaging techniques, and to correlate these findings with behavioral responses. These agents are of high interest as potential treatments for schizophrenia and other mood disorders. Preclinical and phase II clinical data with LY404039 support the hypothesis that metabotropic glutamate receptor subtype 2/3 (mGlu2/3) agonists are a viable, non-dopaminergic strategy for the treatment of schizophrenia. The clinical findings suggest that mGlu2/3 activation is effective in improving both positive and negative symptoms and a study in ketamine-induced working memory deficits in human subjects suggests that cognition can be improved, too. We have recently reported the development of a novel strategy to selectively activate individual mGlu subtypes, particularly mGlu2, using highly selective positive allosteric modulators (PAMs). These compounds do not activate mGlu2 directly, but dramatically potentiate the response of the receptor to Glu. The development of biphenyl indadone-A (BINA), a systemically active mGlu2 PAM that crosses the blood brain barrier, opens an unprecedented opportunity to investigate whether the antipsychotic-like effects of mGlu2/3 agonists can be recapitulated by targeting mGlu2 with a PAM. Our preliminary studies suggest that BINA has robust efficacy in several animal models used to predict antipsychotic efficacy. In the proposed studies, we will utilize BINA and the mGlu2/3 agonist LY404039 in a series of neuroimaging studies to test the hypothesis that selective potentiation of mGlu2 will have activity in animal models that predict antipsychotic efficacy. We hypothesize that these agents will modulate glutamatergic transmission in corticostriatal and corticothalamic circuits and that direct mGlu2/3 activation wil differentially modulate mesolimbic dopamine transmission compared to mGlu2 potentiation. Using resting state functional MRI as an output in NMDA receptor hypofunction models, we predict mGlu2-mediated normalization of neural network fluctuations. We will correlate the imaging findings with treatment effects on cognition tasks. Normalization of resting state brain fluctuations may be an important biomarker of the therapeutic efficacy of antipsychotic agents. PUBLIC HEALTH RELEVANCE: Metabotropic glutamate receptor agonists, such as the mGluR2/3 agonist LY404039, are effective in animal models predictive of antipsychotic-like activity and in improving positive and negative symptoms in schizophrenia. The focus of this application will be to test the hypothesis that selective potentiation of mGluR2 will have efficacy in animal models that predict efficacy in the treatment of schizophrenia similar to the effects of the mGluR2/3 agonist LY404039 used in clinical trials. The overall goals of this proposal are to quantitatively characterize the effects of these compounds on circuits relevant to schizophrenia using functional imaging techniques and to develop translational biomarkers for testing antipsychotic efficacy of potential therapeutic agents. PUBLIC HEALTH RELEVANCE: A family of neurotransmitter receptors called metabotropic glutamate receptors (mGluRs) have emerged as new drug targets for the development of novel treatments for schizophrenia. We will test new agents targeting mGluR subtype-2 in a series of neuroimaging studies in animal models of schizophrenia to determine how activators of this receptor modulate different neurotransmitter systems and brain circuits in vivo. The studies are proposed to directly determine the effects of these agents in brain circuits that may be critically involved in schizophrenia and to accelerate development of imaging biomarker strategies.