Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synaptic strength.
In the mature nervous system, changes in synaptic strength correlate with changes in neuronal structure. Members of the Nogo-66 receptor family have been implicated in regulating neuronal morphology. Nogo-66 receptor 1 (NgR1) supports binding of the myelin inhibitors Nogo-A, MAG (myelin-associated glycoprotein), and OMgp (oligodendrocyte myelin glycoprotein), and is important for growth cone collapse in response to acutely presented inhibitors in vitro. After injury to the corticospinal tract, NgR1 limits axon collateral sprouting but is not important for blocking long-distance regenerative growth in vivo. Here, we report on a novel interaction between NgR1 and select members of the fibroblast growth factor (FGF) family. FGF1 and FGF2 bind directly and with high affinity to NgR1 but not to NgR2 or NgR3. In primary cortical neurons, ectopic NgR1 inhibits FGF2-elicited axonal branching. Loss of NgR1 results in altered spine morphologies along apical dendrites of hippocampal CA1 neurons in vivo. Analysis of synaptosomal fractions revealed that NgR1 is enriched synaptically in the hippocampus. Physiological studies at Schaffer collateral-CA1 synapses uncovered a synaptic function for NgR1. Loss of NgR1 leads to FGF2-dependent enhancement of long-term potentiation (LTP) without altering basal synaptic transmission or short-term plasticity. NgR1 and FGF receptor 1 (FGFR1) are colocalized to synapses, and mechanistic studies revealed that FGFR kinase activity is necessary for FGF2-elicited enhancement of hippocampal LTP in NgR1 mutants. In addition, loss of NgR1 attenuates long-term depression of synaptic transmission at Schaffer collateral-CA1 synapses. Together, our findings establish that physiological NgR1 signaling regulates activity-dependent synaptic strength and uncover neuronal NgR1 as a regulator of synaptic plasticity.
Lee
Hakjoo
H
Department of Biomedical Genetics, Center for Neural Development and Disease, Interdepartmental Graduate Program for Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Raiker
Stephen J
SJ
Venkatesh
Karthik
K
Geary
Rebecca
R
Robak
Laurie A
LA
Zhang
Yu
Y
Yeh
Hermes H
HH
Shrager
Peter
P
Giger
Roman J
RJ
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000502:physiology* / Q000648:ultrastructure; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D058851:GPI-Linked Proteins; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D000070817:Nogo Receptor 2; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D011956:Receptors, Cell Surface / Q000502:physiology*; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure
D058851:GPI-Linked Proteins; D000070817:Nogo Receptor 2; C474327:RTN4RL2 protein, human; D011956:Receptors, Cell Surface