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

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.

SUBMITTER: Omrani A

PROVIDER: S-EPMC5603719 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Omrani A A van der Vaart T T Mientjes E E van Woerden G M GM Hojjati M R MR Li K W KW Gutmann D H DH Levelt C N CN Smit A B AB Silva A J AJ Kushner S A SA Elgersma Y Y

Molecular psychiatry 20150428 11

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. Me ...[more]

PMID: 25917366

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Project description:ImportanceNeurofibromatosis type 1 (NF1) affects hearing through disruption of central auditory processing. The mechanisms, functional severity, and management implications are unclear.ObjectiveTo investigate auditory neural dysfunction and its perceptual consequences in individuals with NF1.Design, setting, and participantsThis case-control study included children and adults with NF1 and control participants matched on age, sex, and hearing level. Patients were recruited through specialist neurofibromatosis and neurogenetic outpatient clinics between April and September 2019. An evaluation of auditory neural activity, monaural/binaural processing, and functional hearing was conducted. Diffusion-weighted magnetic resonance imaging (MRI) data were collected from a subset of participants (10 children with NF1 and 10 matched control participants) and evaluated using a fixel-based analysis of apparent fiber density.Main outcomes and measuresType and severity of auditory dysfunction evaluated via laboratory testing and questionnaire data.ResultsA total of 44 participants (18 [41%] female individuals) with NF1 with a mean (SD) age of 16.9 (10.7) years and 44 control participants (18 [41%] female individuals) with a mean (SD) age of 17.2 (10.2) years were included in the study. Overall, 11 participants (25%) with NF1 presented with evidence of auditory neural dysfunction, including absent, delayed, or low amplitude electrophysiological responses from the auditory nerve and/or brainstem, compared with 1 participant (2%) in the control group (odds ratio [OR], 13.03; 95% CI, 1.59-106.95). Furthermore, 14 participants (32%) with NF1 showed clinically abnormal speech perception in background noise compared with 1 participant (2%) in the control group (OR, 20.07; 95% CI, 2.50-160.89). Analysis of diffusion-weighted MRI data of participants with NF1 showed significantly lower apparent fiber density within the ascending auditory brainstem pathways. The regions identified corresponded to the neural dysfunction measured using electrophysiological assessment.Conclusions and relevanceThe findings of this case-control study could represent new neurobiological and clinical features of NF1. Auditory dysfunction severe enough to impede developmental progress in children and restrict communication in older participants is a common neurobiological feature of the disorder.

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

Publications

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

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