HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1.
Mol Psychiatry
; 20(11): 1311-21, 2015 Nov.
Article
em En
| MEDLINE
| ID: mdl-25917366
ABSTRACT
Cognitive impairments are a major clinical feature of the common neurogenetic disease neurofibromatosis type 1 (NF1). Previous studies have demonstrated that increased neuronal inhibition underlies the learning deficits in NF1, however, the molecular mechanism underlying this cell-type specificity has remained unknown. Here, we identify an interneuron-specific attenuation of hyperpolarization-activated cyclic nucleotide-gated (HCN) current as the cause for increased inhibition in Nf1 mutants. Mechanistically, we demonstrate that HCN1 is a novel NF1-interacting protein for which loss of NF1 results in a concomitant increase of interneuron excitability. Furthermore, the HCN channel agonist lamotrigine rescued the electrophysiological and cognitive deficits in two independent Nf1 mouse models, thereby establishing the importance of HCN channel dysfunction in NF1. Together, our results provide detailed mechanistic insights into the pathophysiology of NF1-associated cognitive defects, and identify a novel target for clinical drug development.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Canais de Potássio
/
Neurofibromatose 1
/
Transtornos Cognitivos
/
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização
Tipo de estudo:
Etiology_studies
Idioma:
En
Revista:
Mol Psychiatry
Assunto da revista:
BIOLOGIA MOLECULAR
/
PSIQUIATRIA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Holanda