Opa1 is essential for retinal ganglion cell synaptic architecture and connectivity.
Retinal ganglion cell dendritic pruning has been reported in association with a 50% reduction in Opa1 transcript and protein in retinal and neural tissue, which manifests as visual dysfunction in the heterozygous mutant mouse, B6;C3-Opa1(Q285STOP). Here we report a marked reduction in retinal ganglion cell synaptic connectivity in the absence of soma loss and explore the mechanism and relationship between mitochondrial integrity and synaptic connectivity. We observed decreased levels of postsynaptic density protein 95 in Opa1(+/-) mutant mice consistent with synaptic loss in the inner plexiform layer. Glutamatergic but not γ-aminobutyric acid-ergic synaptic sites were reduced in Opa1(+/-) mice. We observed increased synaptic vesicle number in bipolar cell terminal arbours assessed by immunohistochemistry, electron microscopy and western blot analysis. These changes occur without significant loss of mitochondrial membrane potential in retina and optic nerve. Analysis of biolistically transfected retinal ganglion cells shows the retraction of mitochondria towards the soma, and mitochondrial fragmentation, preceding dendritic loss. These processes cast light on the intimate relationship between normal mitochondrial fusion and fission balances, as influenced by the OPA1 protein, in neural cell connectivity in the mammalian retina.
FRCOphth, Cardiff School of Optometry Vision Sciences, Maindy Road, Cardiff CF24 4LU, UK.
Pete A
PA
Williams
Malgorzata
M
Piechota
Christopher
C
von Ruhland
Elaine
E
Taylor
James E
JE
Morgan
Marcela
M
Votruba
D000818:Animals; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D018698:Glutamic Acid / Q000378:metabolism; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D009415:Nerve Net / Q000378:metabolism*; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C539582:Med12 protein, mouse; D056892:Mediator Complex; D008565:Membrane Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D051528:Guanylate Kinases