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 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 delta2 type glutamate receptors, as well as Shaker and inward rectifier type K(+) channels, and can mediate clustering of these channels in heterologous cells. Genetic analyses of Drosophila show that MAGUKs play critical roles in synaptic development because mutations of discs large disrupt the subsynaptic reticulum and block postsynaptic clustering of Shaker K(+) 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.
McGee
A W
AW
Department of Physiology and Programs in Biomedical Sciences and Neuroscience, University of California at San Francisco School of Medicine, San Francisco, California 94143-0444, USA.
Topinka
J R
JR
Hashimoto
K
K
Petralia
R S
RS
Kakizawa
S
S
Kauer
F W
FW
Aguilera-Moreno
A
A
Wenthold
R J
RJ
Kano
M
M
Bredt
D S
DS
Kauer
F
F
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001522:Behavior, Animal; D002531:Cerebellum / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D000074288:Discs Large Homolog 1 Protein; D000076122:Disks Large Homolog 4 Protein; D015870:Gene Expression; D018390:Gene Targeting; D051528:Guanylate Kinases; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D013569:Synapses / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
D048868:Adaptor Proteins, Signal Transducing; D000074288:Discs Large Homolog 1 Protein; D000076122:Disks Large Homolog 4 Protein; C000614189:Dlg1 protein, mouse; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; C033652:postsynaptic density proteins; D009703:Nucleoside-Phosphate Kinase; C501445:Dlg2 protein, mouse; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases