Our long term goal is to better understand how neurotransmitter receptor density is maintained and regulated at mature and developing synapses in vivo. We are using the neuromuscular junction (NMJ), an excitatory cholinergic synapse between motor neurons and muscle fibers as our model system, because of the significant impact on human health of disorders at this synapse and because it provides the most accessible model system to study the process of neurotransmitter receptor recycling in vivo. Until recently receptor recycling was thought to be an exclusive property of neurotransmitter receptors in the central nervous system, but we discovered that significant numbers of acetylcholine receptors (AChRs) are recycled back onto the postsynaptic membrane after internalization, contributing to the maintenance of the postsynaptic density of receptors at mature synapses. We will pursue two goals to assess potential roles for recycling during synaptic development and in maturity and two goals to test the roles of molecules that are strong candidates for participation in the recycling process. We have focused on the roles of alpha-dystrobrevin and alpha-syntrophin in regulating the recycling of AChR onto the postsynaptic membrane because mutations in these proteins are clearly associated with human disorders of neuromuscular transmission, and mutations of these genes in mice have been demonstrated to dramatically alter the number of AChR at mature synapses, as might be expected if receptor recycling was aberrant. Understanding the molecular basis of receptor recycling could lead to more effective intervention and therapy that could increase synaptic transmission by increasing AChR number or density in neuromuscular diseases. Furthermore, it seems likely that some aspects of receptor recycling will be common to all cells, so we expect that these results will be useful not only in understanding the development of the neuromuscular junction, but will provide insights into the long-term role of receptor recycling in synaptogenesis and synaptic plasticity at less accessible central synapses.

Public Health Relevance

The accumulation of neurotransmitter receptors directly underneath nerve terminals is essential for healthy transmission of nerve impulses to muscle. The goal of this proposal is to help us better understand the ways by which these receptors are clustered at mature synapses and shaped during the normal development of synaptic connections and develop ways to strengthen these connections when they are weakened by disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047332-09
Application #
8462696
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Porter, John D
Project Start
2003-09-30
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$310,046
Indirect Cost
$103,174
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chen, Po-Ju; Martinez-Pena Y Valenzuela, Isabel; Aittaleb, Mohamed et al. (2016) AChRs Are Essential for the Targeting of Rapsyn to the Postsynaptic Membrane of NMJs in Living Mice. J Neurosci 36:5680-5
Basu, Sreya; Sladecek, Stefan; Martinez de la Peña y Valenzuela, Isabel et al. (2015) CLASP2-dependent microtubule capture at the neuromuscular junction membrane requires LL5β and actin for focal delivery of acetylcholine receptor vesicles. Mol Biol Cell 26:938-51
Aittaleb, Mohamed; Chen, Po-Ju; Akaaboune, Mohammed (2015) Failure of lysosome clustering and positioning in the juxtanuclear region in cells deficient in rapsyn. J Cell Sci 128:3744-56
Brenner, Hans Rudolf; Akaaboune, Mohammed (2014) Recycling of acetylcholine receptors at ectopic postsynaptic clusters induced by exogenous agrin in living rats. Dev Biol 394:122-8
Martinez-Pena y Valenzuela, Isabel; Pires-Oliveira, Marcelo; Akaaboune, Mohammed (2013) PKC and PKA regulate AChR dynamics at the neuromuscular junction of living mice. PLoS One 8:e81311
Mouslim, Chakib; Aittaleb, Mohamed; Hume, Richard I et al. (2012) A role for the calmodulin kinase II-related anchoring protein (ýýkap) in maintaining the stability of nicotinic acetylcholine receptors. J Neurosci 32:5177-85
Martinez-Pena y Valenzuela, Isabel; Mouslim, Chakib; Pires-Oliveira, Marcelo et al. (2011) Nicotinic acetylcholine receptor stability at the NMJ deficient in α-syntrophin in vivo. J Neurosci 31:15586-96
Martinez-Pena y Valenzuela, Isabel; Mouslim, Chakib; Akaaboune, Mohammed (2010) Calcium/calmodulin kinase II-dependent acetylcholine receptor cycling at the mammalian neuromuscular junction in vivo. J Neurosci 30:12455-65
Bruneau, Emile G; Akaaboune, Mohammed (2010) Dynamics of the rapsyn scaffolding protein at the neuromuscular junction of live mice. J Neurosci 30:614-9
Bruneau, Emile G; Brenner, Daniel S; Kuwada, John Y et al. (2008) Acetylcholine receptor clustering is required for the accumulation and maintenance of scaffolding proteins. Curr Biol 18:109-15

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