Research Paper Volume 9, Issue 3 pp 880—899

Functional decline at the aging neuromuscular junction is associated with altered laminin-α4 expression

Kah Meng Lee 1, , Kirat K. Chand 1, 2, , Luke A. Hammond 3, , Nickolas A. Lavidis 1, , Peter G. Noakes 1, 3, ,

  • 1 School of Biomedical Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia
  • 2 University of Queensland Centre for Clinical Research, The University of Queensland, Herston, Queensland 4029, Australia
  • 3 Queensland Brain Institute, The University of Queensland, St. Lucia, Queensland 4072, Australia

received: November 21, 2016 ; accepted: March 3, 2017 ; published: March 14, 2017 ;

https://doi.org/10.18632/aging.101198
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Abstract

Laminin-α4 is involved in the alignment of active zones to postjunctional folds at the neuromuscular junction (NMJ). Prior study has implicated laminin-α4 in NMJ maintenance, with altered NMJ morphology observed in adult laminin-α4 deficient mice (lama4-/-). The present study further investigated the role of laminin-α4 in NMJ maintenance by functional characterization of transmission properties, morphological investigation of synaptic proteins including synaptic laminin-α4, and neuromotor behavioral testing. Results showed maintained perturbed transmission properties at lama4-/- NMJs from adult (3 months) through to aged (18-22 months). Hind-limb grip force demonstrated similar trends as transmission properties, with maintained weaker grip force across age groups in lama4-/-. Interestingly, both transmission properties and hind-limb grip force in aged wild-types resembled those observed in adult lama4-/-. Most significantly, altered expression of laminin-α4 was noted at the wild-type NMJs prior to the observed decline in transmission properties, suggesting that altered laminin-α4 expression precedes the decline of neurotransmission in aging wild-types. These findings significantly support the role of laminin-α4 in maintenance of the NMJ during aging.

Abbreviations

[Ca2+]o: extracellular calcium concentration; α-BTX: alpha-bungarotoxin; AChR: Acetylcholine receptor; EDL: Extensor Digitorum Longus; EPCs: Endplate currents; EPPs: Endplate potentials; HFS: High frequency stimulation; lama4: Laminin alpha 4 gene; mEPCs: Miniature endplate currents; mEPPs: Miniature endplate potentials; NMJ: Neuromuscular junction; NTI: Nerve terminal impulse; PP: Paired-pulse; RMP: Resting membrane potential; RRP: Readily releasable pool; SNAP-25: Synaptosome-associated protein of 25 kDa; SV2: Synaptic vesicle protein 2.