title: Presynaptic NCAM is required for motor neurons to functionally expand their peripheral field of innervation in partially denervated muscles.
abstract: The function of neural cell adhesion molecule (NCAM) expression in motor neurons during axonal sprouting and compensatory reinnervation was explored by partially denervating soleus muscles in mice lacking presynaptic NCAM (Hb9(cre)NCAM(flx)). In agreement with previous studies, the contractile force of muscles in wild-type (NCAM(+/+)) mice recovered completely 2 weeks after 75% of the motor innervation was removed because motor unit size increased by 2.5 times. In contrast, similarly denervated muscles in Hb9(cre)NCAM(flx) mice failed to recover the force lost due to the partial denervation because motor unit size did not change. Anatomical analysis indicated that 50% of soleus end plates were completely denervated 1-4 weeks post-partial denervation in Hb9(cre)NCAM(flx) mice, while another 25% were partially reinnervated. Synaptic vesicles (SVs) remained at extrasynaptic regions in Hb9(cre)NCAM(flx) mice rather than being distributed, as occurs normally, to newly reinnervated neuromuscular junctions (NMJs). Electrophysiological analysis revealed two populations of NMJs in partially denervated Hb9(cre)NCAM(flx) soleus muscles, one with high (mature) quantal content, and another with low (immature) quantal content. Extrasynaptic SVs in Hb9(cre)NCAM(flx) sprouts were associated with L-type voltage-dependent calcium channel (L-VDCC) immunoreactivity and maintained an immature, L-VDCC-dependent recycling phenotype. Moreover, acute nifedipine treatment potentiated neurotransmission at newly sprouted NMJs, while chronic intraperitoneal treatment with nifedipine during a period of synaptic consolidation enhanced functional motor unit expansion in the absence of presynaptic NCAM. We propose that presynaptic NCAM bridges a critical link between the SV cycle and the functional expansion of synaptic territory through the regulation of L-VDCCs.
authors.affiliation: Departments of Medical Neuroscience and.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Chipman
authors.affiliation: Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, New Jersey 08854-8082.
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.affiliation: Departments of Medical Neuroscience and Medicine (Neurology), Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada, Brain Repair Centre, Life Science Research Institute, Halifax, Nova Scotia B3H 4H7, Canada, and vrafuse@dal.ca.
authors.forename: Victor F
authors.initials: VF
authors.lastname: Rafuse
mesh_terms: D000818:Animals; D051927:CD24 Antigen / Q000235:genetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002772:Cholera Toxin / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology* / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009121:Muscle Denervation; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000235:genetics / Q000502:physiology*; D017729:Presynaptic Terminals / Q000502:physiology*; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D020867:omega-Agatoxin IVA / Q000494:pharmacology
chemical_list: D051927:CD24 Antigen; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; C497890:Cd24a protein, mouse; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D014157:Transcription Factors; D020867:omega-Agatoxin IVA; C084059:Hb9 protein, mouse; D002772:Cholera Toxin
keywords: NCAM; neuromuscular junction; partial denervation; regeneration; sprouting
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