McGee, Aaron W.;
Topinka, J. Rick;
Hashimoto, Kouichi;
Petralia, Ronald S.;
Kakizawa, Sho;
Kauer, Frederick;
Aguilera-Moreno, Andrea;
Wenthold, Robert J.;
Kano, Masanobu;
Bredt, David S.
PSD-93 Knock-Out Mice Reveal That Neuronal MAGUKs Are Not Required for Development or Function of Parallel Fiber Synapses in Cerebellum
Beschreibung:
<jats:p>Membrane-associated guanylate kinases (MAGUKs) are abundant postsynaptic density (PSD)-95/discs large/zona occludens-1 (PDZ)-containing proteins that can assemble receptors and associated signaling enzymes at sites of cell–cell contact, including synapses. PSD-93, a postsynaptic neuronal MAGUK, has three PDZ domains that can bind to specific ion channels, including NMDA δ2 type glutamate receptors, as well as Shaker and inward rectifier type K<jats:sup>+</jats:sup>channels, and can mediate clustering of these channels in heterologous cells. Genetic analyses of<jats:italic>Drosophila</jats:italic>show that MAGUKs play critical roles in synaptic development because mutations of<jats:italic>discs large</jats:italic>disrupt the subsynaptic reticulum and block postsynaptic clustering of Shaker K<jats:sup>+</jats:sup>channels. It is uncertain whether MAGUKs play an essential role in the development of central 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 Purkinje neurons from the knock-outs, these mice have no structural or functional abnormality in cerebellum. Both the dendritic architecture and the postsynaptic localization of PSD-93 interacting proteins remain intact at light and electron microscopic levels in the knock-outs. Postsynaptic Purkinje cell responses, monosynaptic climbing fiber innervation, and cerebellar-dependent behaviors are also normal. Our data demonstrate that MAGUK proteins of the PSD-93/95 family are not essential for development of certain central synapses but may instead participate in specialized aspects of synaptic signaling and plasticity.</jats:p>