Rapid compensatory changes in GABA receptor efficacy in rat vestibular neurones after unilateral labyrinthectomy

Abstract

1. The inhibitory effects of the GABAA agonist muscimol and the GABAB agonist baclofen on tonically active medial vestibular nucleus (MVN) neurones were recorded in slices of the rat dorsal brainstem in vitro, to determine whether any changes occurred in the functional efficacy of GABAergic inhibition in these cells during the initial rapid stage of 'vestibular compensation', the behavioural recovery that takes place after unilateral labyrinthectomy (UL). These experiments were carried out in preparations where the midline was cut, severing all commissural connections between the two vestibular nuclei. 2. Slices of the MVN were prepared from normal animals and animals that had been unilaterally labyrinthectomised 4 h earlier. The mean in vitro discharge rate of MVN neurones in the rostral region of the ipsi-lesional nucleus after UL was significantly higher than that in control slices, confirming our earlier reports of an increase in intrinsic excitability of these cells in the early stage of vestibular compensation. The in vitro discharge rates of caudal ipsi-lesional MVN cells, and rostral and caudal contra-lesional MVN cells, were not different from controls. 3. Muscimol and baclofen caused reversible, dose-related inhibition of the tonic discharge rate of MVN cells in control slices. In slices prepared from UL animals, MVN cells in the rostral region of the ipsi-lesional nucleus showed a marked downregulation of their response to both muscimol and baclofen, seen as a rightward shift and a decrease in slope of the dose-response relationships for the two agonists. In the contra-lesional nucleus, there was a small but significant upregulation of the responsiveness of both rostral and caudal MVN cells to baclofen, and a marked upregulation of the responsiveness of caudal MVN cells to muscimol. 4. In slices from animals that had undergone bilateral labyrinthectomy 4 h earlier, the downregulation of the functional efficacy of GABA receptors in the rostral MVN cells did not occur. The changes in GABA receptor efficacy after UL are therefore not due to the vestibular de-afferentation itself, but are instead due to the imbalance in excitability of the vestibular nuclei of the lesioned and intact sides, and the enhanced commissural inhibition of the ipsi-lesional MVN cells that follows UL. 5. The downregulation of GABA receptor efficacy in the ipsi-lesional MVN neurones is functionally compensatory, in that their response to commissural and cerebellar inhibitory drive will be significantly reduced after UL. Their intrinsic membrane conductances, and their remaining excitatory synaptic inputs, will consequently be more effective in causing depolarisation and the restoration of resting activity. Simultaneously the upregulation of GABAergic efficacy in the contra-lesional MVN will tend to reduce the hyperactivity on the contralateral side. These adaptive changes therefore represent a plausible cellular mechanism for the recovery of resting discharge in the ipsi-lesional MVN neurones, and the 'rebalancing' of the excitabi...

Long-Term Plasticity of Ipsilesional Medial Vestibular Nucleus Neurons After Unilateral Labyrinthectomy

“…In particular, we have observed that the proportions of type A and B MVNn were varying along the rostrocaudal extent of the nucleus (N. Vibert, M. Serafin, M. Mühle-thaler, unpublished data). Other authors have demonstrated that the cellular changes associated with vestibular compensation can be different in the caudal and rostral parts of the MVN (Cameron and Dutia 1997;Yamanaka et al 2000). To control for this variability, we decided to restrict as much as possible our recordings to the two 500-m coronal slices corresponding to the middle third of the guinea pig MVN, at the level of the cerebellar peduncles.…”

“…Vestibular compensation involves modification of both the intrinsic properties of the ipsilesional MVNn and the vestibular-related networks in which they are embedded (Cameron and Dutia 1997;Darlington and Smith 1996;Darlington et al 2002;Vibert et al 1999aVibert et al , 2000Yamanaka et al 2000). We recently suggested that in rodents, the spontaneous discharge recovered in vivo by the ipsilesional MVNn might be more and more sustained by changes in the intrinsic properties of MVNn themselves as the time of compensation increases (Vibert et al 1999b).…”

Inactivation of GABAA receptor is related to heat shock stress response in organism model Caenorhabditis elegans

“…We observed that heat shock induced a statistically significant increase in the expression of UNC-49 protein in worms exposed to thermal stress in relation to the non-exposed group. The effect was more apparent in body muscle cells than in head muscle cells and could be a result of a compensatory response to oxidative damage on UNC-49 as reported in other models (Fritschy et al 1999;Yamanaka et al 2000;Zeller et al 2008).…”

Neurobiological Mechanisms of Acute Vertigo

“…Although it is uncontested that the four major neurotransmitters, GABA, glycine, glutamate, and acetylcholine, are involved in the process of neuroplastic changes in VC, a clear picture has not yet emerged, probably because of differences within species. In rats, for example, Yamanaka [34] reported a compensatory down-regulation of inhibitory GABA-A and GABA-B receptors ipsilesional and an upregulation of GABA-B receptors contralesional. Changes in GABA receptor efficacy, thus, could be interpreted in the context of reducing the imbalance between the bilateral MVN [20,34,35].…”

“…In rats, for example, Yamanaka [34] reported a compensatory down-regulation of inhibitory GABA-A and GABA-B receptors ipsilesional and an upregulation of GABA-B receptors contralesional. Changes in GABA receptor efficacy, thus, could be interpreted in the context of reducing the imbalance between the bilateral MVN [20,34,35]. No such changes, however, were found in mice within one week after UVD, while still in mice instead an increase of glutamate receptor activation in the MVN was observed as early as within 4 hours after UVD [36].…”