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Damage to one vestibular apparatus (unilateral vestibular deafferentation, UVD) results in severe postural and ocular motor disturbances (such as spontaneous nystagmus, SN) that recover over time in a process known as vestibular compensation. However, the underlying neurochemical mechanisms of vestibular compensation are poorly understood. While UVD affects many areas in the CNS, attention has focused upon the partially deafferented second order neurons in the vestibular nuclei complex (VNC). Several converging lines of evidence suggest that Ca�⁺-permeable ion channels (N-methyl-D-aspartate receptors and L-type voltage-gated Ca�⁺-channels) and intracellular Ca�⁺-dependent protein kinases play an important role in vestibular compensation. However, the nature of this involvement and the locus of these changes are unknown. The aim of this thesis was to investigate the role of Ca�⁺ signalling pathways in the VNC during vestibular compensation in guinea pig. These issues were investigated in three separate experiments that utilised two methodological approaches: i) in vitro assays were used to determine the nature and extent of protein phosphorylation within the VNC at various stages of compensation; and ii) ion channel blockers or cell-permeable kinase inhibitors were injected directly into the VNC immediately before UVD to determine whether or not these systems were causally involved in compensation. The results of experiment 1 (Chapter 5) showed that a bolus intra-VNC injection of an uncompetitive NMDA receptor antagonist, but not an L-type voltage-gated Ca�⁺ channel antagonist, temporarily reduced SN frequency at the earliest measurement time (6 hours post-UVD). These results suggested that the initial expression of SN required, in part, the activation of NMDA receptors in the VNC on the side of the UVD, and by inference, Ca�⁺ entry through the ion channel. The results of experiment 2 (Chapter 6) revealed that the medial VNC contains abundant Ca�⁺/calmodulin-dependent and Ca�⁺/phospholipid-dependent protein kinase activities. The same VNC tissue removed from animals at various times after UVD, showed that vestibular compensation is accompanied by specific changes in the phosphorylation of several major protein kinase C substrates. These included an unidentified 46-kDa band, and a 75-kDa band with similar characteristics to the myristoylated alanine-rich C kinase substrate (MARCKS). These results suggest that protein kinase C signalling pathways may be involved in vestibular compensation. The results of experiment 3 (Chapter 7) are consistent with these results showing that intra-VNC infusion of a protein kinase C inhibitor, but not a Ca�⁺/calmodulin-dependent protein kinase II inhibitor, significantly increased SN at the earliest measurement times (6 and 8 hours), but had no effect upon the time taken to achieve compensation or on postural compensation. These results suggest that the induction of SN compensation involves protein kinase C activity in the VNC. Taken together, these findings suggest that the mechanisms underlying the expression of SN (e.g., Ca�⁺ influx via NMDA receptors) are possibly distinct from those that initiate its compensation (e.g., PKC activation). The downstream effects of raised intracellular Ca�⁺ may involve protein kinase C-dependent phosphorylation of key intracellular proteins that initiate long-lasting changes in cellular function within the VNC.

Loss of sensory input from one vestibular labyrinth by unilateral vestibular deafferentation (UVD) results in a severe ocular motor (i.e., spontaneous nystagmus (SN)) and postural syndrome (i.e., yaw head tilt, (YHT) and roll head tilt (RHT)) which compensates over time in a behavioural recovery process known as vestibular compensation. It is generally accepted that the UVD-induced neuronal imbalance in the resting activity between the two vestibular nuclear complexes (VNCs) generates the ocular motor and postural syndrome and that the restoration of the resting activity in the ipsilateral VNC plays a causal role in the compensation of the static symptoms. γ-Aminobutyric acid (GABA) and the GABAA and GABAB receptors within the VNC are involved in normal vestibulo-ocular and --spinal pathways and it has been suggested that modification of GABAergic inhibition may be a mechanism responsible for the recovery of resting activity in the ipsilateral VNC. Behavioural, western blotting, and immunoassay techniques were used to address the role of the GABAA receptor in the VNC during vestibular compensation. The first study involved the characterization of SN, YHT, and RHT compensation in guinea pigs that had been anaesthetized with isoflurane during the UVD. These animals compensated rapidly (i.e., 30 hrs) and the time to compensate was independent of the duration of the anaesthesia. Using the 30 hrs time frame, the effects of the chronic infusion of the GABAA receptor agonist (muscimol) / antagonist (gabazine) into either the ipsilateral or the contralateral VNC on the compensation of SN, YHT, and RHT, were determined. Infusion of muscimol (250, 500, and 750 ng) into the contralateral VNC and gabazine (31.25, 62.5 and 125 ng) into the ipsilateral VNC significantly affected YHT and RHT (p < 0.05), but not their rate of compensation (p > 0.05). Interestingly, the effects of muscimol and gabazine on YHT and RHT were consistent throughout the first 30 hrs post-UVD. At 30 hrs post-UVD, the pumps were disconnected. In both experimental groups, the value and direction of the YHT and RHT returned to vehicle levels. Infusion of muscimol (62.5, 125, and 250 ng) into the ipsilateral VNC and gabazine (125, 375, and 750 ng) into the contralateral VNC had little effect on YHT and RHT, or their rate of compensation. At 30 hrs post-UVD, the pumps were disconnected. In both experimental groups, the value and direction of the YHT and RHT returned to vehicle levels. These results suggest that the ipsilateral gabazine and contralateral muscimol infusions were modifying the expression of the symptoms without altering the mechanism of compensation. Furthermore, the mechanism responsible for vestibular compensation can cope with the both the GABAA receptor-mediated and the UVD-induced decrease in resting activity. Results from the western blotting study indicated that compensation of SN, YHT, and RHT is not associated with changes in the protein levels of the GABAA receptor α₁, β₂, or γ₂ subunits. Compensation of SN, YHT, and RHT is associated with an elevation in cortisol salivary levels. Overall, the results suggest that the GABAA receptors are involved in the expression of YHT and RHT, but not in the mechanism that is responsible for their compensation.

Thesis (M. Phil.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Thesis (M.S.)--Ohio University, June, 2006. / Title from PDF t.p. Includes bibliographical references (p. 104-111)