PSD-93 knock-out mice reveal that neuronal MAGUKs are not required for development or function of parallel fiber synapses in cerebellum

Membrane-associated guanylate kinases (MAGUKs) are abundant postsynaptic de nsity (PSD)-95/discs large/zona occludens-1 (PDZ)-containing proteins that can assemble receptors and associated signaling enzymes at sites of cell-ce ll contact, including synapses. PSD-93, a postsynaptic neuronal MAGUK, has three PDZ domains that can bind to specific ion channels, including NMDA de lta2 type glutamate receptors, as well as Shaker and inward rectifier type K+ channels, and can mediate clustering of these channels in heterologous c ells. Genetic analyses of Drosophila show that MAGUKs play critical roles i n synaptic development because mutations of discs large disrupt the subsyna ptic reticulum and block postsynaptic clustering of Shaker K+ channels. It is uncertain whether MAGUKs play an essential role in the development of ce ntral synapses. There are four neuronal MAGUKs with overlapping expression patterns in the mammalian brain; however, we find PSD-93 is the only MAGUK expressed in cerebellar Purkinje neurons. Therefore, we targeted disruption of PSD-93 in mouse. Despite the absence of MAGUK immunoreactivity in Purki nje neurons from the knock-outs, these mice have no structural or functiona l abnormality in cerebellum. Both the dendritic architecture and the postsy naptic localization of PSD-93 interacting proteins remain intact at light a nd electron microscopic levels in the knock-outs. Postsynaptic Purkinje cel l responses, monosynaptic climbing fiber innervation, and cerebellar-depend ent behaviors are also normal. Our data demonstrate that MAGUK proteins of the PSD-93/95 family are not essential for development of certain central s ynapses but may instead participate in specialized aspects of synaptic sign aling and plasticity.