| Summary: | There is currently no effective treatment for the cognitive impairment and psychiatric complications, including depression, associated with the prodromal phase of the development of Huntington's disease (HD). Tianeptine is a clinically used antidepressant, with reported pro-cognitive properties. The ultimate aim of my project was to evaluate in a mouse model of HD the utility of tianeptine as a possible treatment for these prodromal effects. However, although tianeptine shares structural similarities to the tricyclic antidepressant agents, in contrast it has little effect upon serotonin, noradrenaline, or dopamine levels. Therefore, a main focus of the project became an elucidation of the molecular mechanism of action of tianeptine. Previous studies from my host lab revealed, using extracellular recording in the hippocampus, that tianeptine enhanced the dendritic field excitatory postsynaptic potentials (fEPSPs) mediated by glutamate activation of synaptic AMPARs. Using whole-cell voltage-clamp techniques in mouse hippocampal CA1 neurons I demonstrated that tianeptine enhances AMPAR function by a novel mechanism to relieve the block of AMPARs by endogenous polyamines such as spermine. By contrast, I found the AMPAR-enhancing effects of the AMPA-kine CX-614 and of the ketamine metabolite (2R, 6R)-HNK to be polyamine-independent. AMPARs are composed of four subunits drawn from a repertoire of GluA1-4. Spermine selectively blocks the cation-conducting ion channel of "GluA2-lacking" AMPARs. In support, I found that the hippocampal AMPAR-enhancing effect of tianeptine was blunted both in a mouse lacking the GluA1-subunit (GluA1<sup>-/-</sup>) and in a mouse genetically engineered to express an arginine residue instead of a glutamine residue in position 607 located within the ion channel pore of the GluA1 subunit [GluA1(R)]. Collectively these findings reveal in CA1 neurons tianeptine to be selective for GluA1-AMPARs. This effect of tianeptine was prevented by intracellular perfusion of the CA1 neuron with GDPβS, demonstrating that the drug influences AMPAR function indirectly <i>via </i>a postsynaptic G-protein-coupled receptor (GPCR). Recent studies reported tianeptine to be an agonist of µ- and δ-opioid receptors. However, I found the AMPAR-enhancing effects of tianeptine were not influenced by a selective µ-opioid receptor antagonist (CTAP), nor mimicked by a µ-opioid selective agonist (DAMGO). By contrast the AMPAR-enhancing effects of tianeptine were reduced by a selective δ-opioid receptor inverse-agonist (ICI 174,864) and were mimicked byselective δ-opioid agonists (<i>e.g.</i> SNC-80 and DPDPE). In common with tianeptine,the AMPAR-enhancing effect of these δ-opioid receptors was polyamine-dependent. These results identify a novel dialogue between a major excitatory transmitter gatedion channel and an opioid GPCR. Given the current interest in AMPARs as a targetfor rapid acting antidepressants, these findings may be relevant to the efficacy of δopioid receptor agonists as antidepressants. Furthermore, is the function of AMPARsinfluenced by endogenous opioid peptides such as enkephalin and is this mechanismpertinent to the aetiology of depression, a condition associated with perturbed opioidreceptor peptides? Having established a better understanding of the mechanism of action of tianeptine, Inow investigated the AMPAR-enhancing actions of tianeptine in the hippocampus ofjuvenile and adult HdhQ<sup>111+/-</sup> mouse model of Huntington's disease <i>c.f.</i> wild type (WT)littermate. Using tianeptine as a "fingerprint" for GluA1-AMPAR expression, coupledwith immunohistochemistry, I have shown important developmental differences in theexpression of the GluA1 subunit of the HdhQ<sup>111+/-</sup> mouse <i>c.f.</i> WT littermates. Giventhe important role of GluA1-AMPARs in establishing neural networks duringdevelopment and in forms of synaptic plasticity (<i>e.g.</i> long term potentiation - LTP)these findings may permit a better understanding of the development of cognitive andpsychiatric disorders associated with HD.
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