Cerebellar dysfunction results in an inability to smoothly sequence simple movements of appropriate force. This impairment significantly reduces the ability to adapt motor responses to unexpected environmental perturbations. The cerebellum acts to coordinate goal directed movement strategies utilizing a highly ordered, modifiable neural network. Despite a great deal of information on the physiologic inputs to the cerebellum and the anatomical organization of the elements of the network, little is known about the synaptic mechanisms which underlie the integration of multimodal inputs to produce adaptive motor behaviors. Elucidation of the cellular mechanisms which underlie synaptic integration and plasticity in the cerebellum is thus critical to an understanding of its role in both motor learning and movement disorders. The goal of this investigation is to determine the cellular mechanisms of a recently discovered slow excitatory postsynaptic synaptic potential evoked by stimulation of afferent parallel fibers (PF-sEPSP), and to elucidate its contribution to synaptic integration and plasticity in the cerebellum. The turtle cerebellum and combined brainstem-cerebellum provide an exceptional model system for investigation of the cellular bases of complex synaptic systems. The turtle exhibits a unique resistance to anoxia which enables the intact brain, or isolated brain structures, to be maintained in vitro for several days with no decrement in physiologic function with the attendant advantages of in vitro preparations for intracellular recording. To determine the cellular basis of PF-sEPSP generation, ion-sensitive microelectrodes will be employed in conjunction with intracellular recording techniques to test the hypothesis that, with phasic stimulation, tightly packed parallel fibers are unable to rapidly remove high levels of extracellular potassium, resulting in an increased or prolonged release of transmitter and generation of the PF-sEPSP. Both pressure ejection of potassium at parallel fiber synapses and analysis of levels of presynaptic release with phasic stimulation will be utilized to further evaluate this hypothesis. The receptor which mediates sEPSP generation will be determined by a combination of agonist application to intracellularly recorded neurons and pharmacologic blockade by selective antagonists. The relevance of the PF-sEPSP to synaptic integration and plasticity in the cerebellar cortex will be determined using the brainstem-cerebellum preparation which allows stimulation of appropriate afferent systems coupled with intracellular impalement of target neurons. The results of this study should provide a better understanding of the cellular mechanisms which underlie sensory integration and synaptic plasticity in the cerebellum.
| Lu, H; Larson-Prior, L J (1996) Serotonergic modulation of evoked responses in turtle cerebellar Purkinje cells. J Neurophysiol 76:3102-13 |
