HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1.

Omrani, Azar. and van der Vaart, Taco. and Mientjes, Edwin. and van Woerden, Geeke.M. and Hojjati, Mohammad reza. and Li, K.W. and Gutmann, David.H. and Levelt, Christiaan. and Smit, A.B. and Silva, Ana. and Kushner, S.A. and Elgersma, Y.pe. (2015) HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1. Molecular psychiatry, 20 (11). pp. 1311-21. ISSN 1476-5578

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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.

Item Type: Article
Subjects: WL Nervous system
WM Psychiatry
Divisions: Faculty of Medicine > Basic Sciences Academic Groups > Department of Physiology
Depositing User: zahra bagheri .
Date Deposited: 26 Jul 2017 04:36
Last Modified: 08 May 2018 07:43
URI: http://eprints.skums.ac.ir/id/eprint/1780

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