This is an F31 application that seeks 3-yrs of training support to conduct alcohol studies in the laboratory of an established alcohol researcher who will serve as the applicant mentor for this project. Ethanol exposure has been shown to cause significant changes in neuronal signaling and morphology, particularly at glutamatergic synapses. During chronic ethanol exposure, homeostatic processes are engaged to restore the balance between excitatory and inhibitory input. These compensatory changes are characterized by an increase in N- methyl d- aspartate (NMDA) receptor surface expression and structural changes at synapses that include an enlargement of dendritic spines. We present preliminary evidence that this homeostatic response also includes a decrease in the A-type voltage-gated K+-channels (IA) Kv4.2 that are highly expressed in dendritic spines. However, the regulatory mechanisms driving these homeostatic changes are unknown. Recent studies indicate the K+-channel interacting protein 3 (KChIP3) may have an influential role in controlling the balance between excitatory and inhibitory inputs. KChIP3 has recently been shown to have a dual function to promote the surface expression of Kv4.2 channels while inhibiting the surface expression of NMDA receptors. Preliminary data further indicates KChIP3 is also down regulated in response to chronic ethanol exposure. This observations support the overarching hypothesis of this proposal that changes in surface expression of NMDA receptors and Kv4.2 channels represent a coupled homeostatic process mediated by a chronic ethanol- induced reduction in expression of KChIP3. This over-arching hypothesis will be testing through three sets of studies as as follows:
Aim 1 will test the hypothesis that KChIP3 mediates chronic ethanol-induced changes in expression and trafficking of NMDA receptors and Kv4.2 channels;
Aim 2 will Test the hypothesis that chronic ethanol-induced changes in the structure and function of glutamatergic synapses can be reversed by over- expression of KChIP3;
Aim 3 will test the hypothesis that chronic ethanol-induced changes in NMDA receptors, Kv4.2 channels, and KChIP3 are mediated by FMRP. The proposed studies and related training plan will not only enhance the career development of the applicant, but the results obtained will significantly advance our understanding of the regulatory mechanisms influencing neuroplasticity of alcohol dependence and addiction.
Chronic ethanol consumption causes significant, long-term neuroadaptations in glutamatergic neurotransmission that may play a significant role in alcohol dependence and addition. Thus, this project will elucidate the regulatory mechanism controlling the compensatory changes in NMDA receptors and Kv4.2 channels. Results from this work could facilitate the development of novel pharmacotherapeutics to treat alcohol use disorders.
|Spencer, Kathryn B; Mulholland, Patrick J; Chandler, L Judson (2016) FMRP Mediates Chronic Ethanol-Induced Changes in NMDA, Kv4.2, and KChIP3 Expression in the Hippocampus. Alcohol Clin Exp Res 40:1251-61|
|Mulholland, Patrick J; Spencer, Kathryn B; Hu, Wei et al. (2015) Neuroplasticity of A-type potassium channel complexes induced by chronic alcohol exposure enhances dendritic calcium transients in hippocampus. Psychopharmacology (Berl) 232:1995-2006|