Psd-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2

Postsynaptic density protein 95 (PSD-95) is essential for synaptic maturation and plasticity. Although its synaptic regulation is widely studied, the control of PSD-95 cellular expression is not understood. We find that Psd-95 is controlled post-transcriptionally during neural development. Psd-95 is transcribed early in mouse embryonic brain, but most of its product transcripts are degraded. The polypyrimidine tract binding proteins, PTBP1 and PTBP2, repress Psd-95 exon 18 splicing, leading to premature translation termination and nonsense-mediated mRNA decay (NMD). The loss first of PTBP1 and then of PTBP2 during embryonic development allows splicing of Exon 18 and expression of PSD-95 late in neuronal maturation. Re-expression of PTBP1 or PTBP2 in differentiated neurons inhibits PSD-95 expression and impairs development of glutamatergic synapses. Thus, expression of PSD-95 during early neural development is controlled at the RNA level by two PTB proteins whose sequential down-regulation is necessary for synapse maturation.