Neurobiological aspects of depression- Antidepressant effects on glia-neuron interaction

Major depressive disorder (MDD) is a globally spread and complex neuropsychiatric disorder. The neurobiological underpinnings of MDD are a current matter of study. The strong heterogeneity of its clinical manifestations and the lack of response in some patients make the identification of new targets and the generation of novel treatments an important issue for the treatment of MDD. Therefore, the aim of this thesis was to contribute to the discovery of new targets for antidepressants (ADs) to improve MDD treatment. Recently, it was shown in post-morten tissue of MDD patients that the number of glial cells is reduced, accompanied by atrophy of neuronal cells and decreased volume of the prefrontal cortex (PFC). Neuropsychiatric disorders also display disrupted synaptic communication and neuronal connectivity, which are reversed by ADs. Following the hypothesis that a dysregulation in the communication between glial cells and neurons is one of the key factors underlying the development of MDD, I aimed to see the effects of astrocytes on synapse homeostasis upon the effect of ADs. I focused my study on the PFC and hippocampal areas, hence these areas are known to be highly involved in mood disorders. For examining cell-type specificity, I performed both in vitro and ex vivo experiments from naïve animals in order to not interfere with other physiological changes produced by the disease itself. In the present study, I could observe a reduction in excitatory synaptic densities in vitro, after 48h continuous AD treatment, when neurons were growing in the presence of cortical astrocytes but not when hippocampal astrocytes were present. In the absence of astrocytes or in the presence Astrocyte-Neuron Conditioned Media such effects were not seen, suggesting that a membrane-bound protein might have mediated those effects. Ex vivo experiments also revealed a reduction of synaptic markers in the adult rat PFC after short-term treatment with ADs, but not in other areas such as CA1 and CA3 of the hippocampus. Astrocytes could mediate this fast AD action as there are closely associated to synapses. For these reasons, MEGF10 receptor was studied. This molecule is a transmembrane receptor that participates in synapse elimination mostly during development. Indeed, treatment with ADs for 48 hours (h) triggered an increase in MEGF10 expression in the adult rat PFC and in primary cultured astrocytes. Therefore, the reduction in the number of synaptic densities I observed could be explained by an astrocyte-dependent 10 remodelling of synapses following acute AD treatment. In support of this hypothesis, the downregulation of MEGF10 was sufficient to block ADs effects, thus no reduction in synaptic densities was observed. Taken together, these data suggest that MEGF10 could be a potential novel candidate to develop alternative treatment options for diseases characterized by synaptic aberrancies, such as MDD. Moreover, it is important to understand which major changes are produced in disease conditions. Therefore, part of this thesis aimed to demonstrate the neurobiological basis of the heterogeneity found in depression, using two different animal models with a depressive-like phenotype (HAB, High Anxiety like Behaviour rat and WK, Wistar Kyoto rat). Differences in the number of synaptic densities and in the morphology of neurons have been found in HAB and WK compared to control animals. Finally, further studies should reveal the contribution of MEGF10 to such changes and how a pharmacological treatment may help to re-establish some of those changes