Neurodevelopmental disorders (NDDs) are prevalent neurodevelopmental conditions which affected 3% of general population without effective treatment so far. Among the NDD candidate genes, mutations in PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked Intellectual Disability (ID) and Autism Spectrum Disorders (ASD). The aim of the study is deciphering the molecular and cellular role of PTCHD1 in brain development and understanding its pathological impact leading to NDD.To dissect the molecular mechanisms allowing PTCHD1 receptor interactions at synapse, we first applied co-immunoprecipitation and GST pull down assays using synaptosomal fractions from mouse cortices and then performed proximity ligation assays and immunocytochemistry at neuronal and synaptic level. We also assessed the impact of Ptchd1 deletion on the global expression of the hippocampal synaptic proteome in Ptchd1 KO mouse model using Mass-spectrometry analyses and immunoblotting.As a result, we found that the C-terminal region of PTCHD1, can interact with Rac1, a RhoGTPase essential for cytoskeleton activity and remodeling, and synapse plasticity, associated with NDDs. Furthermore, we highlighted a significant increase in PAK1 protein expression and a decrease in ERK protein in hippocampi from Ptchd1-/y mice. Preliminary results revealed a possible role of PTCHD1 in regulating activation of ERK pathway.To conclude, we highlighted PTCHD1 novel interacting partner and associated signaling pathways at synapse, allowing a better understanding of its synaptic role and thus revealing a potential future therapeutic target for NDDs.