The Role of PAK Signaling in Synaptic Transmission and Plasticity and Social Memory in Mice

Social interactions are essential to our mental health and their deficits are hallmark characteristics in numerous brain disorders. Various subregions within the medial temporal lobe have been implicated in social memory, however, the underlying molecular and cellular mechanisms that tune these particular neural circuits in memory processing remain unclear. PAKs (p21-activated kinases) are a family of serine/threonine protein kinases that are target enzymes of the Rho family small GTPases and central regulators of both the actin cytoskeleton and neuronal morphology. PAK 1 and 3 are involved in the regulation of the structural and functional properties of the synapse, including dendritic spine morphology, synaptic transmission and plasticity, and learning and memory. Recent human and animal studies have revealed that perturbations in PAKs are implicated in several neurological and mental disorders including autism spectrum disorders (ASD) and intellectual disability (ID). These disorders are often characterized by social impairments, yet the cellular correlates within the neural circuits that subserve PAK function in social behaviour remains unknown. In this thesis, I explore five objectives which elucidates the role of PAK signaling in the entorhinal cortical perforant projections to the dentate gyrus (EC-DG) in social memory retrieval. First, I characterize the biochemical and cellular properties of a novel transgenic mouse model where the expression of a dominant negative mutation of PAK3 can be temporally and spatially controlled. Second, I demonstrate that the reversible disruption of PAK signaling impairs social recognition memory without affecting other behavioural responses. Third, using electrophysiological recording and imaging techniques, I show that presynaptic neurotransmitter release is specifically impaired at the EC-DG synapse in the mutant mice. Fourth, I use biochemical analyses and show that cofilin and the actin cytoskeleton are significantly altered in the mutant mice. Lastly, I demonstrate that acute optogenetic manipulation of the EC-DG terminals is sufficient to rescue the social memory deficits in the PAK3 transgenic mouse model. Together, these results identify a novel signaling pathway mediated by PAKs within the EC-DG circuit that governs social memory retrieval. Furthermore, these findings suggest potential circuit and molecular mechanisms important for the treatment of social disorders.Ph.D