POSH participates in epileptogenesis by increasing the surface expression of the NMDA receptor: a promising therapeutic target for epilepsy.
Expert Opin Ther Targets
; 21(12): 1083-1094, 2017 12.
Article
em En
| MEDLINE
| ID: mdl-29057721
ABSTRACT
OBJECTIVES:
Plenty of SH3 (POSH) was originally found to be a key regulator of neuronal apoptosis, axon outgrowth, and neuronal migration. However, the role of POSH in epilepsy has not been reported.METHODS:
We investigated the expression of POSH in patients with intractable temporal epilepsy (TLE) and in a kainic acid (KA)-induced mouse model, and then we performed behavioral, electrophysiological and biochemical analyses after the lentivirus (LV)-mediated knockdown or overexpression of POSH in the KA-induced model.RESULTS:
POSH overexpression shortened the latency of seizure onset, increased the frequency of spontaneous recurrent seizures, and increased the frequency of electrical epileptic discharges, while POSH knockdown had contrasting effects. Whole-cell patch-clamp recordings confirmed that POSH overexpression and knockdown were associated with increased and decreased miniature excitatory postsynaptic currents (mEPSCs) and N-methyl-D-aspartate receptor (NMDAR)-mediated currents, respectively. Finally, co-immunoprecipitation showed that POSH and NMDA receptor subunit 1 (NMDAR1) precipitated with each other, and western blot analysis revealed that the surface expression of NMDAR1 was altered in the hippocampus of epileptic mice.CONCLUSION:
These results show that POSH plays a critical role in the progression of epileptic seizures via NMDAR trafficking and suggest that the protein is a novel target for the treatment of human epilepsy.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores de N-Metil-D-Aspartato
/
Ubiquitina-Proteína Ligases
/
Epilepsia do Lobo Temporal
/
Terapia de Alvo Molecular
Limite:
Adolescent
/
Adult
/
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article