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

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Bibliographic Details
Title:	HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1.
Authors:	Omrani, A, van der Vaart, T, Mientjes, E, van Woerden, G M, Hojjati, M R, Li, K W, Gutmann, D H, Levelt, C N, Smit, A B, Silva, A J, Kushner, S A, Elgersma, Y
Source:	Molecular Psychiatry. Nov2015, Vol. 20 Issue 11, p1311-1321. 11p.
Subjects:	Cognition disorders, Neurofibromatosis 1, Hyperpolarization (Cytology), Cyclic nucleotides, Protein-protein interactions, Genetics
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. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
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. [ABSTRACT FROM AUTHOR]
ISSN:	13594184
DOI:	10.1038/mp.2015.48