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PNAS 101 (36): 13346-13351

Copyright © 2004 by the National Academy of Sciences.

From The Cover


NEUROSCIENCE

The immunoglobulin family member dendrite arborization and synapse maturation 1 (Dasm1) controls excitatory synapse maturation

Song-Hai Shi, Tong Cheng, Lily Yeh Jan, and Yuh-Nung Jan *

Howard Hughes Medical Institute and Department of Physiology and Biochemistry, University of California, 1550 4th Street, San Francisco, CA 94143-0725

Contributed by Yuh-Nung Jan, July 26, 2004

Abstract: In the developing mammalian brain, a large fraction of excitatory synapses initially contain only N-methyl-D-aspartate receptor and thus are "silent" at the resting membrane potential. As development progresses, synapses acquire {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs). Although this maturation of excitatory synapses has been well characterized, the molecular basis for this developmental change is not known. Here, we report that dendrite arborization and synapse maturation 1 (Dasm1), an Ig superfamily member, controls excitatory synapse maturation. Dasm1 is localized at the excitatory synapses. Suppression of Dasm1 expression by using RNA interference or expression of dominant negative deletion mutants of Dasm1 in hippocampal neurons at late developmental stage specifically impairs AMPA-R-mediated, but not N-methyl-D-aspartate receptor-mediated, synaptic transmission. The ability of Dasm1 to regulate synaptic AMPA-Rs requires its intracellular C-terminal PDZ domain-binding motif, which interacts with two synaptic PDZ domain-containing proteins involved in spine/synapse maturation, Shank and S-SCAM. Moreover, expression of dominant negative deletion mutants of Dasm1 leads to more immature silent synapses. These results suggest that Dasm1, as a transmembrane molecule, likely provides a link to bridge extracellular signals and intracellular signaling complexes in controlling excitatory synapse maturation.


Abbreviations: Dasm1, dendrite arborization and synapse maturation 1; NMDA, N-methyl-D-aspartate; NMDA-R, NMDA receptor; AMPA, {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AMPA-R, AMPA receptor; EGFP, enhanced GFP; EPSC, excitatory postsynaptic current; mEPSC, miniature EPSC; RNAi, RNA interference; trans, transfected; untrans, untransfected; inf, infected; uninf, uninfected.

* To whom correspondence should be addressed. E-mail: ynjan{at}itsa.ucsf.edu.

© 2004 by The National Academy of Sciences of the USA

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