| Summary: | 碩士 === 長庚大學 === 生物醫學研究所 === 100 === Parkinson’s disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the substantia nigra (SN), which then results in basal ganglia dysfunction and motor deficits. The subthalamic nucleus (STN) is an important structure involved in the shaping of the basal ganglia activity. Increased burst firing activity in STN has been a hallmark in the pathophysiology of PD. Moreover, high-frequency deep brain stimulation (DBS) of the STN effectively improves the motor symptoms in many PD patients. However, the casual relation between subthalamic burst activity and motor disabilities of PD remains to be established. The cellular mechanisms underlying STN bursts and the DBS therapy are also unclear.
In this study, we first characterized Ca2+ channels in acutely dissociated STN neurons from the rat brain based on the electrophysiological and pharmacological properties of different Ca2+ channels. We demonstrated the existence of both low-voltage activated (LVA or T-type) Ca2+ channels and high-voltage activated (HVA) Ca2+ channels in dissociated STN neurons. We then investigated the possible contribution of T-type and HVA Ca2+ channels to the firing pattern of STN neurons in acute mouse brain slices. We found that T-type Ca2+ channel inhibitors (e.g. Ni2+ and miberfradil) but not HVA Ca2+ channel inhibitors (e.g. Cd2+ and nifedipine) suppress burst firing or even turn burst into spiking pattern of firing in STN slices. Subsequently, we performed whole-cell current-clamp recording of STN neurons to directly monitor the membrane potential changes with DBS-mimicking electrodes being placed onto STN. We found that extracellular injection of negative constant currents into STN by the DBS-mimicking electrodes depolarizes STN neurons and diminishes burst firing of STN, an effect ascribable to a decrease in the availability of T-type Ca2+ channels. Not only intrinsic neuronal membrane properties but also synaptic inputs that a neuron receives would, in theory, determine the discharge patterns in STN. STN neurons chiefly receive excitatory synaptic inputs from the cortex and inhibitory GABAergic inputs from the globus pallidus (GP). Our preliminary resluts showed that stimulation of GP would evoke GABAergic inhibitory postsynaptic currents (IPSC) in STN, and the GP-STN synapse exhibits short-term synaptic depression.
We conclude that T-type Ca2+ channel should essentially contribute to the burst pattern of firing in STN. Moreover, the effect of DBS therapy could rely on adequate membrane depolarization and thus T-type Ca2+ channel inactivation in STN neurons. Modulation of subthalamic firing pattern could therefore be a possible strategy for the treatment of Parkinson’s disease.
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