Activity-dependent volume transmission by transgene NPY attenuates glutamate release and LTP in the subiculum.
Neuropeptide Y (NPY) gene transduction of the brain using viral vectors in epileptogenic regions can effectively suppress seizures in animals, and is being considered as a promising alternative treatment strategy for epilepsy. Therefore, it is fundamental to understand the detailed mechanisms governing the release and action of transgene NPY in neuronal circuitries. Using whole-cell recordings from subicular neurons, we show that in animals transduced by recombinant adeno-associated viral (rAAV) vector carrying the NPY gene, transgene NPY is released during high-frequency activation of CA1-subicular synapses. Released transgene NPY attenuates excitatory synaptic transmission not only in activated, but also in neighboring, non-activated synapses. Such broad action of transgene NPY may prevent recruitment of excitatory synapses in epileptic activity and could play a key role in limiting the spread and generalization of seizures.
Sørensen
Andreas T
AT
Experimental Epilepsy Group, Wallenberg Neuroscience Center, Lund University Hospital, Lund, Sweden.
Kanter-Schlifke
Irene
I
Lin
En-Ju D
EJ
During
Matthew J
MJ
Kokaia
Merab
M
D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D055592:Biophysical Phenomena; D016009:Chi-Square Distribution; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D005822:Genetic Vectors / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics* / Q000502:physiology; D008297:Male; D009474:Neurons / Q000502:physiology; D009478:Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010751:Phosphopyruvate Hydratase / Q000235:genetics / Q000378:metabolism; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors; D013779:Tetrodotoxin / Q000494:pharmacology; D019076:Transgenes / Q000502:physiology*
D001120:Arginine; D001552:Benzazepines; D018756:GABA Antagonists; D018698:Glutamic Acid; D049452:Green Fluorescent Proteins; D009478:Neuropeptide Y; D010751:Phosphopyruvate Hydratase; D010852:Picrotoxin; D017476:Receptors, Neuropeptide Y; D013779:Tetrodotoxin; C403256:BIIE 0246