Activity of nAChRs containing alpha9 subunits modulates synapse stabilization via bidirectional signaling programs.
Although the synaptogenic program for cholinergic synapses of the neuromuscular junction is well known, little is known of the identity or dynamic expression patterns of proteins involved in non-neuromuscular nicotinic synapse development. We have previously demonstrated abnormal presynaptic terminal morphology following loss of nicotinic acetylcholine receptor (nAChR) alpha9 subunit expression in adult cochleae. However, the molecular mechanisms underlying these changes have remained obscure. To better understand synapse formation and the role of cholinergic activity in the synaptogenesis of the inner ear, we exploit the nAChR alpha9 subunit null mouse. In this mouse, functional acetylcholine (ACh) neurotransmission to the hair cells is completely silenced. Results demonstrate a premature, effusive innervation to the synaptic pole of the outer hair cells in alpha9 null mice coinciding with delayed expression of cell adhesion proteins during the period of effusive contact. Collapse of the ectopic innervation coincides with an age-related hyperexpression pattern in the null mice. In addition, we document changes in expression of presynaptic vesicle recycling/trafficking machinery in the alpha9 null mice that suggests a bidirectional information flow between the target of the neural innervation (the hair cells) and the presynaptic terminal that is modified by hair cell nAChR activity. Loss of nAChR activity may alter transcriptional activity, as CREB binding protein expression is decreased coincident with the increased expression of N-Cadherin in the adult alpha9 null mice. Finally, by using mice expressing the nondesensitizing alpha9 L9'T point mutant nAChR subunit, we show that increased nAChR activity drives synaptic hyperinnervation.
Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA.
Vidya
V
Murthy
Julián
J
Taranda
A Belén
AB
Elgoyhen
Douglas E
DE
Vetter
D000109:Acetylcholine / Q000378:metabolism*; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001306:Auditory Pathways / Q000378:metabolism; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000378:metabolism; D007758:Ear, Inner / Q000294:innervation / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
D015815:Cell Adhesion Molecules; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D000109:Acetylcholine