Proline-rich tyrosine kinase 2 (Pyk2) is a calcium-dependent non-receptor tyrosine kinase of the focal adhesion kinase (FAK) family, enriched in forebrain neurons. In this thesis, I studied Pyk2 in neuropathological conditions in vivo, using total or conditional knock-out mice. Pyk2 deficit in the hippocampus resulted in alterations of NMDA receptors, PSD-95 and dendritic spines. These defects were associated with an impairment of CA1 LTP and hippocampal-related learning thus confirming the crucial importance of Pyk2 in the expression of synaptic plasticity. Huntington’s and Alzheimer’s diseases were associated with decreased in total Pyk2 or its activated forms in hippocampus. Overexpression of Pyk2 using adeno-associated virus rescued synaptic properties and memory deficits. In parallel with this main project, we showed the efficacy of astrocytic delivery of BDNF (a known activator of Pyk2) in a mouse model of Alzheimer’s disease. Conversely, deletion of Pyk2 in the amygdala prevented spine alterations and development of depressive-like symptoms induced by chronic unpredictable stress. Finally, in the striatum, Pyk2 deficiency was not associated with the synaptic defects observed in other brain areas. However, it decreased locomotor response to acute cocaine injection without altering locomotor sensitization and conditioned place preference. This phenotype was recapitulated by deletion of Pyk2 in the nucleus accumbens or in D1 receptor-expressing neurons suggesting a specific role of Pyk2 in these neurons. Taken together this work supports an important role for Pyk2 in synapses and shows that its alteration contributes to the development of neurological disorders.