Cortical and Pallidal Modulation of Parkinsonian Subthalamic Discharges

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Parkinson’s disease (PD) is one of the most prevalent movement disorder caused by degeneration of the midbrain dopaminergic neurons. The dopaminergic input to the striatum and the subthalamic nucleus (STN) is therefore decreased, apparently resulting in significant derangements in the relevant motor-planning networks. STN neurons could discharge in the singe-spike or the burst modes. A significant increase in STN burst discharges has been unequivocally observed in dopamine-deprived conditions such as PD. Recently, we demonstrated that the increase in burst discharges of subthalamic neurons has a direct causal relation with parkinsonian symptoms, and that alterations of membrane potential could switch the discharge pattern of subthalamic neurons between the singe spikes and the pathogenic bursts. In theory, the membrane potential and the firing pattern of a neuron would be influenced by the intrinsic membrane properties of the cell and the sum of excitatory and inhibitory synaptic inputs. Dopamine and other neuromodulators have been reported to affect the intrinsic membrane properties of STN by modulation of different kinds of ion channels. However, the synaptic influences on the subthalamic pathogenic discharges remain largely unclear. Subthalamic neurons receive direct excitatory and inhibitory synaptic inputs from the cortex and the external segment of the globus pallidus (GPe), respectively. We hypothesize that the GABAergic inputs from GPe probably constitute the major external hyperpolarizing drive for the subthalamic neurons and may therefore shift the firing mode from tonic firings to (rhythmic or semirhythmic) bursts. On the other hand, the cortico-subthalamic glutamatergic projection presumably may provide either a phasic depolarizing force to start a discharge (in single-spike or burst mode) or a tonic depolarizing force to make the neuron favor single-spike discharges upon subsequent phasic stimulation. We would therefore propose to test these hypotheses and study the contributions of cortico-subthalamic and pallido-subthalamic synaptic inputs to subthalamic discharges in detail. We will characterize the basic properties, such as the strength and short-term plasticity, of cortico-subthalamic and pallido-subthalamic synaptic transmission in acute mouse brain slices. The computation of the excitatory and inhibitory synaptic inputs over multiple temporal and spatial scales will be investigated. Their consequences in the coding of electrical signals such as discharge patterns and timing will be documented, and possible effects on the physiological and pathophysiological information processing in the relevant networks will be discussed. We will also explore the neuromodulatory effects of dopamine, norepinephrine, serotonin, and acetylcholine (all of which are known to have innervations onto the STN neurons) on the synaptic transmission and plasticity in the cortico-subthalamic and pallido-subthalamic pathways. Moreover, the influences of cortico-subthalamic and pallido-subthalamic synaptic information on the subthalamic pathogenic discharges will be verified with experimentally mimicked parkinsonian state both in vivo and in vitro. With the execution of this proposal, we shall have more in-depth understandings of the critical cortical and pallidal synaptic drives that determine subthalamic discharge outputs, and thus would be able to elucidate more fundamental physiological as well as pathophysiological rationales underlying the operation of the motor-planning networks in the normal and parkinsonian mammalian brain.

Project IDs

Project ID:PA10501-1098
External Project ID:MOST103-2311-B182-001-MY3
StatusFinished
Effective start/end date01/08/1631/07/17

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