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

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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]
Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1.
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  Data: <searchLink fieldCode="AR" term="%22Omrani%2C+A%22">Omrani, A</searchLink><br /><searchLink fieldCode="AR" term="%22van+der+Vaart%2C+T%22">van der Vaart, T</searchLink><br /><searchLink fieldCode="AR" term="%22Mientjes%2C+E%22">Mientjes, E</searchLink><br /><searchLink fieldCode="AR" term="%22van+Woerden%2C+G+M%22">van Woerden, G M</searchLink><br /><searchLink fieldCode="AR" term="%22Hojjati%2C+M+R%22">Hojjati, M R</searchLink><br /><searchLink fieldCode="AR" term="%22Li%2C+K+W%22">Li, K W</searchLink><br /><searchLink fieldCode="AR" term="%22Gutmann%2C+D+H%22">Gutmann, D H</searchLink><br /><searchLink fieldCode="AR" term="%22Levelt%2C+C+N%22">Levelt, C N</searchLink><br /><searchLink fieldCode="AR" term="%22Smit%2C+A+B%22">Smit, A B</searchLink><br /><searchLink fieldCode="AR" term="%22Silva%2C+A+J%22">Silva, A J</searchLink><br /><searchLink fieldCode="AR" term="%22Kushner%2C+S+A%22">Kushner, S A</searchLink><br /><searchLink fieldCode="AR" term="%22Elgersma%2C+Y%22">Elgersma, Y</searchLink>
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  Data: <searchLink fieldCode="JN" term="%22Molecular+Psychiatry%22">Molecular Psychiatry</searchLink>. Nov2015, Vol. 20 Issue 11, p1311-1321. 11p.
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  Data: <searchLink fieldCode="DE" term="%22Cognition+disorders%22">Cognition disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Neurofibromatosis+1%22">Neurofibromatosis 1</searchLink><br /><searchLink fieldCode="DE" term="%22Hyperpolarization+%28Cytology%29%22">Hyperpolarization (Cytology)</searchLink><br /><searchLink fieldCode="DE" term="%22Cyclic+nucleotides%22">Cyclic nucleotides</searchLink><br /><searchLink fieldCode="DE" term="%22Protein-protein+interactions%22">Protein-protein interactions</searchLink><br /><searchLink fieldCode="DE" term="%22Genetics%22">Genetics</searchLink>
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  Data: 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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  Data: <i>Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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