TY - JOUR

T1 - Over-expression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions

AU - Chee, Francis C

AU - Mudher, Amritpal

AU - Cuttle, Matthew F

AU - Newman, Tracey A

AU - MacKay, Daniel

AU - Lovestone, Simon

AU - Shepherd, David

PY - 2005/12

Y1 - 2005/12

N2 - We have shown that over-expression of human tau (0N3R) in Drosophila larval motor neurons causes significant morphological and functional disruption to the neuromuscular junctions (NMJs). Tau-expressing NMJs are reduced in size with irregular and abnormal bouton structure. Immunocytochemical analysis shows that the abnormal NMJs still retain synaptotagmin expression and form active zones. Functionally, the NMJs exhibit abnormal endo/exocytosis as revealed by incorporation of the styryl dye FM1-43. Electrophysiological studies showed that with low frequency stimulation (1 Hz), evoked synaptic potentials produced from tau over-expressing motor neurons were indistinguishable from wild type, however, following high frequency stimulation (50 Hz), evoked synaptic potentials were significantly decreased. Analysis of the number and distribution of mitochondria showed that motor neurons over-expressing tau had a significant reduction in functional mitochondria in the presynaptic terminal. Collapsing the mitochondrial membrane potential in wild type larvae phenocopied the effects of tau over-expression on synaptic transmission. Our results demonstrate that tau over-expression in vivo cause a synaptic dysfunction, which may be caused by a reduced complement of functional mitochondria.

AB - We have shown that over-expression of human tau (0N3R) in Drosophila larval motor neurons causes significant morphological and functional disruption to the neuromuscular junctions (NMJs). Tau-expressing NMJs are reduced in size with irregular and abnormal bouton structure. Immunocytochemical analysis shows that the abnormal NMJs still retain synaptotagmin expression and form active zones. Functionally, the NMJs exhibit abnormal endo/exocytosis as revealed by incorporation of the styryl dye FM1-43. Electrophysiological studies showed that with low frequency stimulation (1 Hz), evoked synaptic potentials produced from tau over-expressing motor neurons were indistinguishable from wild type, however, following high frequency stimulation (50 Hz), evoked synaptic potentials were significantly decreased. Analysis of the number and distribution of mitochondria showed that motor neurons over-expressing tau had a significant reduction in functional mitochondria in the presynaptic terminal. Collapsing the mitochondrial membrane potential in wild type larvae phenocopied the effects of tau over-expression on synaptic transmission. Our results demonstrate that tau over-expression in vivo cause a synaptic dysfunction, which may be caused by a reduced complement of functional mitochondria.

KW - Animals

KW - Animals, Genetically Modified

KW - Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology

KW - Cell Respiration/drug effects

KW - Disease Models, Animal

KW - Drosophila

KW - Electric Stimulation

KW - Excitatory Postsynaptic Potentials/genetics

KW - Exocytosis/genetics

KW - Green Fluorescent Proteins

KW - Humans

KW - Larva

KW - Mitochondria/drug effects

KW - Motor Neurons/metabolism

KW - Mutation/genetics

KW - Neuromuscular Junction/metabolism

KW - Neuromuscular Junction Diseases/genetics

KW - Presynaptic Terminals/metabolism

KW - Synaptic Transmission/genetics

KW - Synaptotagmin I/metabolism

KW - Tauopathies/genetics

KW - tau Proteins/genetics

U2 - 10.1016/j.nbd.2005.05.029

DO - 10.1016/j.nbd.2005.05.029

M3 - Article

C2 - 16023860

VL - 20

SP - 918

EP - 928

JO - Neurobiology of disease

JF - Neurobiology of disease

SN - 0969-9961

IS - 3

ER -