EPIGENETIC HOMEOSTATIC MECHANISM IN NEURONAL ADAPTATION AND METAPLASTICITY TO ENVIRONMENTAL STIMULI

It is widely known that environmental stress represents a driving factor for the onset of mental illnesses, common multifactorial disorders that cause a strong deterioration of the quality of life. Upon a stressful event the glutamatergic system is strongly engaged in many brain areas, in particular the hippocampus. Upon acute stress, glutamatergic transmission is boosted in order to promptly respond to the incoming threat and to allow the consolidation of stressful memories to respond to similar future events. However, thanks to homeostatic synaptic plasticity mechanisms devoted to stress coping, no long-term stress-related negative consequences occur. A different scenario is represented by chronic stress. Upon continuous unpredictable series of stresses glutamatergic transmission is altered, since stress-coping mechanisms might fail. This could result, in vulnerable individuals, in the development of neuropsychiatric disorders. The aim of my PhD work was to investigate the function of the epigenetic corepressor LSD1 and of its brain-specific dominant negative isoform neuroLSD1 in the transcriptional mechanisms underlying neuronal plasticity and affecting complex emotional and cognitive behaviors. In particular, I focused on the role of these enzymes in stress response, a process that entails memorization of the traumatic event but that, at the same time, requires homeostatic mechanisms to avoid a too vivid memorization of the stressful event. We hypothesize that the modulation of the ratio of LSD1 isoforms that occurs upon psychosocial stress is implicated in this homeostasis, with the aim of buffering stress response and the consequent memory consolidation of the traumatic event. Through molecular, biochemical, ultrastructural, electrophysiological and behavioral approaches we tried to test this hypothesis. We found that stress-dependent LSD1 isoforms shift towards a repressive layout (increase of LSD1 and decrease of neuroLSD1) is engaged upon NMDAr activation. This is supported by in vitro and in vivo experimental data; indeed blockade of the NMDAr with MK-801 hampers neuroLSD1 downregulation. Thanks to a pharmacological approach that specifically downregulates neuroLSD1, we observed a negative modulation of basal glutamatergic transmission in terms of frequency and amplitude of mEPSCs. Moreover, we found a less responsive post-synaptic density from a biochemical, electrophysiological and structural point of view in neuroLSD1-/- mice. Furthermore, analyzing human hippocampal samples we found that neuroLSD1 decreases along with aging, supporting a role in the negative modulation of memory processes. In parallel, I focused my studies on the endocannabinoid system, another player implicated in this homeostatic process. In particular, I found a crosstalk among LSD1 isoforms and the endocannabinoid system in restraining glutamatergic neuroplasticity in response to stress-induced glutamate release thought the transcriptional repression of ABHD6 and MAGL, the degradative enzymes of the endocannabinoid 2-arachidonyl glycerol. From our data we can conclude that these nuclear and synaptic processes might participate in a converging complex negative feedback mechanism aimed at decreasing stress-induced glutamatergic signaling in the hippocampus, promoting stress termination and possibly the buffering of memory consolidation.