UC San Diego

The signaling mechanisms of regulating excitatory synapses are the foundation for understanding neural circuit functions and disorders but have not been fully understood. Previously our lab has found an opposing role of core planar cell polarity (PCP) components, Celsr3 and Vangl2, in regulating excitatory synapse formation. Celsr3 is required for excitatory synapse formation, while Vangl2 inhibits excitatory synapse formation. Here, we took a further step to focus on another PCP component called Prickle. We found that the deletion of Prickle homolog 2 (Prickle2/Pk2) in developing and adult mice’s dorsal hippocampus and medial prefrontal cortex (mPFC) reduced the density of excitatory synapses. Moreover, Prickle2 p.E8Q mutation, which was found in human patients diagnosed with Autism Spectrum Disorder (ASD), reduced the density of excitatory synapses in the stratum radiatum of mice CA1 region. The reduced synapse density may be due to the decreased level of NMDA receptors, AMPA receptors, and MAGUK family proteins that are essential for synapse development. We also found that the Prickle2 p.E8Q protein was less stable than WT Prickle2, which may be due to the increased interaction between Prickle2 and Vangl2 that enhanced the proteasomal degradation of Prickle2. In addition, in HEK293T cells, Prickle2 interacted with Prickle homolog 1 (Prickle1/Pk1), which contributes to ASD and epilepsy. In mice’s stratum radiatum of CA1 region and layer I-III of mPFC, Prickle2 and Prickle1 colocalized with each other while both colocalized with postsynaptic density 95 (PSD-95). These data together indicated Prickle2 plays an essential role in regulating synapse formation and function.