PTPRO Governs Synaptic Density, Long-Term Potentiation and Cognitive Function In Vivo

Protein Tyrosine Phosphatase Receptor Type O (PTPRO) is a synaptic cell adhesion molecule that is essential for synapse formation in vitro; however, its in vivo role remains unclear. Using PTPRO-knockout mice, we found that PTPRO deletion reduced the number of synapses and impaired both excitatory and inhibitory synaptic transmission. PTPRO knockout also disrupted hippocampal long-term potentiation and caused learning and memory deficits in the water maze as well as in fear conditioning. Notably, overexpression of the N-terminal extracellular domain of PTPRO rescued the frequencies of miniature excitatory postsynaptic currents and inhibitory postsynaptic currents, indicating that this domain is required to regulate synapse number and transmission. Collectively, these data demonstrate that PTPRO is essential for maintaining synapse number, synaptic transmission, long-term potentiation, and learning and memory functions in vivo.