Young DAPK1 knockout mice have altered presynaptic function.

The death-associated protein kinase 1 (DAPK1) has recently been shown to have a physiological function in long-term depression (LTD) of glutamatergic synapses: acute inhibition of DAPK1 blocked the LTD that is normally seen at the hippocampal CA1 synapse in young mice, and a pharmacogenetic combination approach showed that this specifically required DAPK1-mediated suppression of postsynaptic Ca/calmodulin-dependent protein kinase II binding to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B during LTD stimuli. Surprisingly, we found here that genetic deletion of DAPK1 (in DAPK1 mice) did not reduce LTD. Paired pulse facilitation experiments indicated a presynaptic compensation mechanism: in contrast to wild-type mice, LTD stimuli in DAPK1 mice decreased presynaptic release probability. Basal synaptic strength was normal in young DAPK1 mice, but basal glutamate release probability was reduced, an effect that normalized with maturation. Young death-associated protein kinase 1 (DAPK1) knockout mice have reduced basal glutamate release probability, an effect that normalized with maturation. This provided a compensatory mechanism that may have prevented a reduction of long-term depression in the young DAPK1 knockout mice.