Overexpression of the cell adhesion protein neuroligin-1 induces learning deficits and impairs synaptic plasticity by altering the ratio of excitation to inhibition in the hippocampus.
Trans-synaptic cell-adhesion molecules have been implicated in regulating CNS synaptogenesis. Among these, the Neuroligin (NL) family (NLs 1-4) of postsynaptic adhesion proteins has been shown to promote the development and specification of excitatory versus inhibitory synapses. NLs form a heterophilic complex with the presynaptic transmembrane protein Neurexin (NRX). A differential association of NLs with postsynaptic scaffolding proteins and NRX isoforms has been suggested to regulate the ratio of excitatory to inhibitory synapses (E/I ratio). Using transgenic mice, we have tested this hypothesis by overexpressing NL1 in vivo to determine whether the relative levels of these cell adhesion molecules may influence synapse maturation, long-term potentiation (LTP), and/or learning. We found that NL1-overexpressing mice show significant deficits in memory acquisition, but not in memory retrieval. Golgi and electron microscopy analysis revealed changes in synapse morphology indicative of increased maturation of excitatory synapses. In parallel, electrophysiological examination indicated a shift in the synaptic activity toward increased excitation as well as impairment in LTP induction. Our results demonstrate that altered balance in the expression of molecules necessary for synapse specification and development (such as NL1) can lead to defects in memory formation and synaptic plasticity and outline the importance of rigidly controlled synaptic maturation processes.
Dahlhaus
Regina
R
Department of Psychiatry, University of British Columbia, Vancouver, BC.
Hines
Rochelle M
RM
Eadie
Brennan D
BD
Kannangara
Timal S
TS
Hines
Dustin J
DJ
Brown
Craig E
CE
Christie
Brian R
BR
El-Husseini
Alaa
A
D000818:Animals; D001921:Brain / Q000503:physiopathology / Q000648:ultrastructure; D015816:Cell Adhesion Molecules, Neuronal; D049229:Dendritic Spines / Q000502:physiology / Q000648:ultrastructure; D006624:Hippocampus / Q000503:physiopathology* / Q000648:ultrastructure; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000473:pathology / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009433:Neural Inhibition / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology*
D015816:Cell Adhesion Molecules, Neuronal; D019006:Neural Cell Adhesion Molecules; C093438:neuroligin 1