Glutamate Receptors in the Medial Temporal Lobe Following Bilateral Vestibular Deafferentation

Abstract

Dysfunction of the vestibular system can be caused by a number of conditions including Meniere‘s disease and aminoglycoside antibiotic induced damage. Bilateral vestibular damage results in symptoms such as vertigo, dysequilibrium and dysfunctional eye movements. Studies of vestibular loss have also documented decreases in the volume of the hippocampus, and electrophysiological changes such as alterations in place cell activity and theta rhythm. The hippocampus is an area of the brain associated with memory and learning, and vestibular damage can result in long-term cognitive problems, including spatial and non-spatial memory deficits. It is poorly understood what molecular changes occur in the hippocampus that lead to these alterations in function and structure. This study measured N-methyl-D-aspartic acid (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors levels in the entorhinal cortex (EC), perirhinal cortex, frontal cortex (FC) and the CA1, CA2/3 and dentate gyrus (DG) sub-regions of the rat hippocampus, at 24 hours, 72 hours, 1 week and 1 month following bilateral vestibular deafferentation (BVD) surgery. NMDA and AMPA receptor subunit levels were assessed because they are the two of the most important classes of ionotropic glutamate receptors in the hippocampus and are known to be involved in synaptic plasticity and memory. The protein kinase CaMKII and its active form, phosphorylated CaMKII, were also measured post-BVD, as it is a downstream signalling molecule that has a role in both NMDA and AMPA receptor activity. There was no significant difference between BVD and sham animals in the expression of individual receptor subunits in any of the brain regions at any time point following a one way analysis of variance. However, two multivariate statistical analysis techniques were used to analyse the relationship between variables within the treatment groups linear discriminant analysis detected a linear discriminant function based on 8 variables from these data that could distinguish between BVD and sham rats with 100% accuracy. These variables were: CaMKII at 24 hours in the DG, GluR2 at 1 week in the CA1, GluR4 at 1month in the EC, NR1 at 1 week in the CA1, NR1 at 1 week in the DG, NR1 at 1 month in the DG, NR1 at 1 month in the FC and NR2B at 1 month in the FC. Cluster analysis provided further information on the relationship between these 8 variables following BVD surgery. These results indicate that while the expression of individual glutamate receptor subunits did not change significantly when comparing BVD rats with controls that had undergone sham surgery, there was a change in the relationship between these variables following bilateral vestibular loss. Although BVD results in a number of electrophysiological and behavioural alterations, the neurochemical changes appear to be more subtle and spread across a number of brain regions. Further studies need to be performed to assess changes in NMDAR and AMPAR affinity, efficacy and neuronal location in the medial temporal lobe of BVD animals.