Epileptiform activity and cognitive deficits in SNAP-25(+/-) mice are normalized by antiepileptic drugs.
Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs.
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, 20129 Milan, Italy.
Irene
I
Corradini
Andrea
A
Donzelli
Flavia
F
Antonucci
Hans
H
Welzl
Maarten
M
Loos
Roberta
R
Martucci
Silvia
S
De Astis
Linda
L
Pattini
Francesca
F
Inverardi
David
D
Wolfer
Matteo
M
Caleo
Yuri
Y
Bozzi
Claudia
C
Verderio
Carolina
C
Frassoni
Daniela
D
Braida
Mario
M
Clerici
Hans-Peter
HP
Lipp
Mariaelvina
M
Sala
Michela
M
Matteoli
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001245:Association Learning / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002220:Carbamazepine / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004827:Epilepsy / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005013:Ethosuximide / Q000627:therapeutic use; D006948:Hyperkinesis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009553:Nimodipine / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism*; D014635:Valproic Acid / Q000627:therapeutic use
D000927:Anticonvulsants; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25; D002220:Carbamazepine; D009553:Nimodipine; D005013:Ethosuximide; D014635:Valproic Acid; D007608:Kainic Acid