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Title: Group II metabotropic glutamate receptor modulation of sensory responses in the ventrobasal thalamus
Author: Copeland, C. S.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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The functional integrity of the thalamic reticular nucleus (TRN) is thought to be key in the control of selective attention (Crick, 1984; Pinault, 2004). This GABAergic structure (Houser et al., 1980) is responsible for ensuring synchronous activity within the appropriate thalamocortical circuits required for either sensory perception or for the preparation and execution of distinct motor and/or cognitive tasks. It is therefore imperative to ascertain the exact nature of how inhibitory innervation from the TRN to thalamic nuclei is controlled in order to understand how neurophysiological disease states associated with TRN malfunction (Huguenard, 1999; Rub et al., 2003; Barbas and Zikopoulos, 2007; Pinault, 2011) precipitate. I t has been previously demonstrated that the Group II metabotropic glutamate receptors (mGlu2/3) can modulate physiologically-evoked responses in the VB (Salt and Turner, 1998) by reducing inhibition from the TR N (Turner and Salt, 2003). However, it is not yet known what the relative contributions are of the two subtypes to this modulation, nor to what extent these receptors may be activated under physiological conditions during this process. Using single-neurone recording in the rat ventrobasal thalamus (VB) in vivo with local iontophoretic application of selective Group II mGlu receptor compounds, my findings were threefold. Firstly, I found that both mGlu2 and mGlu3 receptors contribute a component to the overall Group II mGlu receptor effect on sensory responses in the VB. Secondly, I was able to demonstrate that both Group II mGlu receptor subtypes are likely activated by endogenous ‘glutamate spillover’ from the synapses formed between excitatory sensory afferents and VB neurones following physiological sensory stimulation, and that this can lead to a reduction in sensory-evoked inhibition arising from the TRN. I propose that this potential Group II mGlu receptor modulation of inhibition could play an important role in discerning relevant information from background activity upon physiological sensory stimulation: a novel mechanism that could be of importance in attention and cognitive processes, whose malfunction could result in maladaption of sensory perception, such as that which can occur in psychiatric disease. Thirdly, I was able to provide evidence that mGlu2 receptors are likely located on astrocytic processes surrounding the VB- TR N synapse, and are able to mediate a n a st rocyti c mechanism of action that reduces inhibitory synaptic transmission from the TRN to the VB. To the best of my knowledge this provides the first evidence that mGlu2 receptors are able to activate astrocytes, and of the involvement of astrocytes in the modulation of heterosynaptic transmission. As VB astrocytes are able to respond to synaptic stimulation (Parri et al., 2010), maladaption of mGlu2 receptor-mediated endogenous astrocytic activation may therefore have functional implications for the processing of somatosensory information and for the preparation and execution of distinct motor and/or cognitive tasks. Finally, I also investigated the action of the putative endogenous selective Group II mGlu receptor agonist Xanthurenic Acid (XA), which is a metabolite of the kynurenine pathway. Changes in both of these systems have been implicated in the pathophysiology of schizophrenia and other psychiatric disorders, however little is known regarding the mechanism of action of XA. I therefore investigated the effects of XA in modulating inhibition in the VB from the TRN using the same in vivo electrophysiology preparation as described above, and also evaluated the ability of XA to bind to and activate mGlu2 receptors using in vitro molecular pharmacological methods. Selective Group II mGlu receptor compounds that exploit this novel mechanism of endogenous activation may therefore be of importance in the modulation of sensory, attentional and cognitive processes for therapeutic strategies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available