Cysteine string protein-alpha prevents activity-dependent degeneration in GABAergic synapses.
The continuous release of neurotransmitter could be seen to place a persistent burden on presynaptic proteins, one that could compromise nerve terminal function. This supposition and the molecular mechanisms that might protect highly active synapses merit investigation. In hippocampal cultures from knock-out mice lacking the presynaptic cochaperone cysteine string protein-alpha (CSP-alpha), we observe progressive degeneration of highly active synaptotagmin 2 (Syt2)-expressing GABAergic synapses, but surprisingly not of glutamatergic terminals. In CSP-alpha knock-out mice, synaptic degeneration of basket cell terminals occurs in vivo in the presence of normal glutamatergic synapses onto dentate gyrus granule cells. Consistent with this, in hippocampal cultures from these mice, the frequency of miniature IPSCs, caused by spontaneous GABA release, progressively declines, whereas the frequency of miniature excitatory AMPA receptor-mediated currents (mEPSCs), caused by spontaneous release of glutamate, is normal. However, the mEPSC amplitude progressively decreases. Remarkably, long-term block of glutamatergic transmission in cultures lacking CSP-alpha substantially rescues Syt2-expressing GABAergic synapses from neurodegeneration. These findings demonstrate that elevated neural activity increases synapse vulnerability and that CSP-alpha is essential to maintain presynaptic function under a physiologically high-activity regimen.
García-Junco-Clemente
Pablo
P
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Cientificas, Universidad de Sevilla, Sevilla, Spain.
Cantero
Gloria
G
Gómez-Sánchez
Leonardo
L
Linares-Clemente
Pedro
P
Martínez-López
José A
JA
Luján
Rafael
R
Fernández-Chacón
Rafael
R
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000502:physiology; D001640:Bicuculline / Q000494:pharmacology; D002478:Cells, Cultured; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018682:GABA Agents / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D013569:Synapses / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018683:Excitatory Amino Acid Agents; D018682:GABA Agents; D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C088460:cysteine string protein; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D001640:Bicuculline