title: Altered active zones, vesicle pools, nerve terminal conductivity, and morphology during experimental MuSK myasthenia gravis.
abstract: Recent studies demonstrate reduced motor-nerve function during autoimmune muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). To further understand the basis of motor-nerve dysfunction during MuSK-MG, we immunized female C57/B6 mice with purified rat MuSK ectodomain. Nerve-muscle preparations were dissected and neuromuscular junctions (NMJs) studied electrophysiologically, morphologically, and biochemically. While all mice produced antibodies to MuSK, only 40% developed respiratory muscle weakness. In vitro study of respiratory nerve-muscle preparations isolated from these affected mice revealed that 78% of NMJs produced endplate currents (EPCs) with significantly reduced quantal content, although potentiation and depression at 50 Hz remained qualitatively normal. EPC and mEPC amplitude variability indicated significantly reduced number of vesicle-release sites (active zones) and reduced probability of vesicle release. The readily releasable vesicle pool size and the frequency of large amplitude mEPCs also declined. The remaining NMJs had intermittent (4%) or complete (18%) failure of neurotransmitter release in response to 50 Hz nerve stimulation, presumably due to blocked action potential entry into the nerve terminal, which may arise from nerve terminal swelling and thinning. Since MuSK-MG-affected muscles do not express the AChR γ subunit, the observed prolongation of EPC decay time was not due to inactivity-induced expression of embryonic acetylcholine receptor, but rather to reduced catalytic activity of acetylcholinesterase. Muscle protein levels of MuSK did not change. These findings provide novel insight into the pathophysiology of autoimmune MuSK-MG.
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School-Rutgers University, Newark, New Jersey, United States of America.
authors.forename: Vishwendra
authors.initials: V
authors.lastname: Patel
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School-Rutgers University, Newark, New Jersey, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Oh
authors.affiliation: Department Cell Biology and Molecular Medicine, New Jersey Medical School-Rutgers University, Newark, New Jersey, United States of America.
authors.forename: Antanina
authors.initials: A
authors.lastname: Voit
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School-Rutgers University, Newark, New Jersey, United States of America.
authors.forename: Lester G
authors.initials: LG
authors.lastname: Sultatos
authors.affiliation: Department Cell Biology and Molecular Medicine, New Jersey Medical School-Rutgers University, Newark, New Jersey, United States of America.
authors.forename: Gopal J
authors.initials: GJ
authors.lastname: Babu
authors.affiliation: Department of Microbiology, University of Illinois, Urbana-Champaign, Illinois, United States of America.
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Wilson
authors.affiliation: Department of Microbiology, University of Illinois, Urbana-Champaign, Illinois, United States of America.
authors.forename: Mengfei
authors.initials: M
authors.lastname: Ho
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School-Rutgers University, Newark, New Jersey, United States of America.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: McArdle
mesh_terms: D000818:Animals; D005260:Female; D007116:Immunization, Passive; D051379:Mice; D009045:Motor Endplate / Q000473:pathology / Q000503:physiopathology; D009046:Motor Neurons / Q000473:pathology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D009431:Neural Conduction; D018377:Neurotransmitter Agents / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism*; D014611:Vaccination
chemical_list: D018377:Neurotransmitter Agents; D011950:Receptors, Cholinergic; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases