The role of Homer1a-mediated regulation of glutamatergic signalling in the antidepressant therapy

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Major depressive disorder is the most common mental diseases. The widely used monoamine-based antidepressant drugs require weeks to month to improve symptoms, have low response rates and often cause side effects. Therefore, the search for mechanistically novel and more effective therapeutic options for depression is currently a research priority.We have identified that the synaptic plasticity protein Homer1a is an important element for the antidepressant therapy. The modulation of glutamate receptors activity has been proposed as a promising target for development of rapid-acting antidepressant drugs. In the previous funding period, we investigated Homer1a as modulator of glutamatergic signalling and demonstrated that its antidepressant effects depend on metabotropic glutamate receptor 5 (mGluR5) signaling and enhanced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) function. Moreover, we have introduced a novel approach utilizing systemic administration of cell-penetrable TAT-peptides, which elicit rapid antidepressant effects modulating directly the activity of different glutamatergic receptors.In the present proposal, we plan to further characterize the antidepressant mechanism of action of these TAT-peptides after intranasal application that will allow better brain targeting, enhanced efficacy and clinical validity. Our data suggest that Homer1a-mGluR5 activity differentially affects depression-like behavior, sleep function and synaptic plasticity depending on the brain region and type of neurons targeted. Accordingly, we aim to investigate further the importance of mGluR5 modulation in different brain regions and neuronal population for the homeostatic plasticity, sleep regulation and antidepressant treatment. In addition to regulating glutamatergic signaling within mPFC, Homer1a is also implicated in the modulation of dopaminergic system. Thus, we plan to test the hypothesis that Homer1a affects mood regulation and motivational processing via influencing the dopaminergic signaling within mesolimbic reward circuitry.The ultimate goal of our project is to contribute in the long-run, by better characterization of the molecular and cellular mechanisms of the rapid antidepressant response, to the generation of more selective and efficacious drugs. Moreover, the intranasal application of TAT-peptides targeting glutamatergic system could lead to the development of novel and specific therapeutic strategies for treatment of depression.