Compromissione del comportamento olfattivo e dinamiche neuronale alterate nei topi mutanti per oligophrenin1.

Neurodevelopmental disorders (NDDs), encompassing conditions like intellectual disability (ID) and autism spectrum disorder (ASD), exhibit a wide variety of cognitive, social, and adaptive deficits. Understanding the etiopathogenesis of such disorders is complicated by the absence of a singular explanation for their origins, as they emerge from an intricate combination of genetic, environmental and prenatal causes. However, a subset of ID-ASD-associated pathologies emerges from monogenic causes, being linked to distinct single gene mutations on the X-chromosome, such as FMR1, PAK3, and OPHN1. OPHN1 encodes a Rho GTPase-activating protein (Rho-GAP): it acts as a molecular switch controlling the activation state of Rho GTPases. As a consequence, absence of OPHN1 is characterized by a persistent activity of Rho GTPases and their relative downstream signaling pathways (such as, RhoA/ROCK). OPHN1 plays a crucial role in neuronal development, particularly in brain areas with high plasticity like the neocortex, the hippocampus, and the olfactory bulb (OB). As a Rho-GAP, OPHN1 mediates various intracellular pathways influencing spine and dendrite morphology, synaptic function, and integration. Despite substantial in vitro research on OPHN1, a gap remains in in vivo evidence demonstrating its impact on the brain function. This Ph.D. project focused on elucidating OPHN1's role in behavioral and neuronal network dynamics using a validated mouse model lacking this gene (i.e., ophn1-/y), specifically studying the olfactory bulb (OB). The OB, integral to olfactory processing, emerges as a relevant area due to its high OPHN1 expression, involvement in early neurodevelopmental pathologies, and connections with higher brain regions involved in the processing of sensory and cognitive functions, impaired in ID-ASD pathologies. This study revealed significant alterations in olfactory guided behavior in ophn1-/y mice, without gross impairments in their exploratory activity. Electrophysiological recordings in awake animals freely behaving allowed us to characterize ophn1-/y’s phenotype in different frequency bands of oscillations. In particular, we observed a reduction in power in the high-gamma band, and an increased power in beta oscillations, compared to WT – during both active exploration and resting phases. These abnormalities are crucial as these frequency bands contribute to the sensory processing of the olfactory information, as well as to odorant discrimination and learning, involving a wider network of brain areas, including the piriform cortex. Furthermore, two-photon calcium imaging uncovered abnormal stimulus-evoked activity in ophn1-/y mice, affecting calcium activity amplitude and delay upon odorant stimulation. Mutant animals displayed less correlated activity and a reduced complexity in network organization, indicating altered olfactory computation. Ultimately, we administered a medically approved RhoA/ROCK inhibitor, Fasudil, to alleviate the impact of OPHN1 deficiency. Remarkably, the olfactory behavioral phenotype was entirely rescued, though electrophysiological recordings revealed only a partial recovery in the local field potentials (LFPs) within the olfactory bulb (OB). This comprehensive approach shed light on OPHN1's role in neurodevelopmental pathologies, emphasizing the importance of in vivo investigations for an integral understanding of neuronal network dynamics and their underlying computations in neurodevelopmental pathologies. Such evidence is essential to design effective therapeutic approaches.