Intracellular signaling dynamic control of synaptic responses in the basal ganglia

Oregon Health & Science University, Portland OR

Investigators

Abstract

Project Summary The external globus pallidus (GPe) is a central hub nucleus that processes information necessary for behavioral control by the basal ganglia, a group of interconnected forebrain nuclei. A wide range of behavioral disorders, including the formation of obsessive and compulsive habits, and the generation of psychotic, major depressive, and anxiety disorders are all thought to arise by dysfunctions of the basal ganglia because these nuclei process a wide range of information. Sensorimotor, associative, and cognitive information from many regions of the cortex and thalamus are integrated by projection neurons of the striatum, the main basal ganglia input nucleus. In order for the basal ganglia to control behavior, information from the striatum must then be integrated by the GPe. In the rodent, where the connectivity of the basal ganglia is best quantified, millions of striatal projection neurons (SPNs) form hundreds of millions of inhibitory synapses on only tens of thousands of GPe neurons. Each GPe neuron has two unique properties that may allow them to process an enormous amount of information: long dendrites and spontaneous somatic firing. The long dendrites of GPe neurons allow them to receive an enormous number of inhibitory striatal synaptic inputs, but also force these inputs to propagate along the dendrites before they can be integrated by the somata as changes in firing. The spontaneous firing of GPe neurons is driven by intracellular second messengers that activate two protein kinases that can enhance dendritic propagation. The goal of this proposal is to investigate how dendritic protein kinase activity (1) relates to the spontaneous firing activity of GPe neurons and (2) controls their integration of inhibitory striatal synaptic inputs. To address these questions, this proposal is divided into two aims. (Aim 1) Determine the relationship between dendritic protein kinase activity and spontaneous firing activity in GPe neurons. I will receive training in two-photon fluorescence lifetime microscopy to measure the spatiotemporal dynamics of dendritic protein kinase activity, while simultaneously measuring the spontaneous firing activity of GPe neurons using the cell-attached technique. (Aim 2) Determine how protein kinase activity controls the spike time responses of GPe neurons to dendritic input from the striatum. I will receive training in laser scanning photostimulation to selectively evoke dendritic striatal inputs, and will employ perforated patch clamp recordings to measure the effect of blocking protein kinase activity on the integration of these dendritic inputs. The proposed work will advance our understanding of information processing within the basal ganglia and will broaden my research approach. I will perform the proposed work under the mentorship of Dr. Tianyi Mao, a pioneer in the design and use of optical techniques to measure the spatiotemporal dynamics of protein kinase activity and the integration of dendritic synaptic inputs, at the Vollum Institute, a world-renowned research institute that has advanced our understanding of synaptic transmission and intracellular effector functions for the past four decades.