Cerebellar glutamate receptor antagonism and vestibulo-ocular reflex adaptation: Implications for learning and memory.

摘要

Vestibulo-ocular reflex adaptation has served as a model system for investigating neuroplasticity within the sensori-motor system. This reflex helps to maintain clear vision during head movement by generating eye movements that are equal in velocity and opposite in direction to that of the head. Reflex adaptation is induced by a mismatch of visual and vestibular stimulation, resulting in a progressive change in the magnitude of the reflex, leading to the elimination of image slip. The 3 neuron vestibulo-ocular reflex arc with cerebellar side loop responsible for the adaptation provides a relatively simple model for studying neuroplasticity.; Antagonists to glutamate receptor subtypes (NMDA, AMPA/kainate and metabotropic) have been shown to interfere with neuroplastic phenomena in the central nervous system (i.e., hippocampal long-term potentiation and cerebellar long-term depression). Currently, no other work has examined the role of glutamate in vestibulo-ocular reflex adaptation in vivo. However, glutamate and its respective receptor subtypes have been localized in the cerebellum and vestibular nuclei, the two brain areas responsible of vestibulo-ocular reflex adaptation.; The studies described in this thesis used vestibulo-ocular reflex adaptation in the goldfish to investigate the involvement of glutamate receptor pharmacology in sensori-motor plasticity. Results of these studies showed that localized vestibulo-cerebellar infusion of the glutamate receptor antagonists scD-AP5, CNQX, and L-AP3 that respectively inhibit the NMDA, AMPA/kainate and metabotropic receptors, blocked an increase in the gain of the reflex. Also, scD-APS and CNQX inhibited retention of this adapted gain increase. In contrast, L-AP3 prolonged retention of a previously adapted gain increase. CNQX was the only compound that blocked both the acquisition and retention phases of an adapted gain decrease in the reflex. This work demonstrates that the gain increase adaptation requires activation of NMDA, AMPA/kainate and metabotropic receptors and only the AMPA/kainate receptors are essential for decrease adaptation. The differences between the increase and decrease adaptation indicate that these two tasks involve different pharmacologic mechanisms and/or anatomical structures within a common reflex circuitry. These findings suggest that adaptive gain increases of the vestibulo-ocular reflex and long-term depression share similar glutamate receptor pharmacology and may be related.