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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cognition Disorders / drug therapy*
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Cognition Disorders / etiology
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Cognition Disorders / genetics
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Cognition Disorders / metabolism*
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Disease Models, Animal
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Excitatory Amino Acid Antagonists / therapeutic use
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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Hippocampus / cytology
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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics
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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism*
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Lamotrigine
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Male
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Maze Learning / drug effects
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Maze Learning / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Motor Activity / drug effects
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Motor Activity / genetics
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Mutation / genetics
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Neural Inhibition / drug effects
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Neural Inhibition / genetics
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Neurofibromatosis 1 / complications*
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Neurofibromatosis 1 / genetics
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Neurofibromin 1 / genetics
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Neurofibromin 1 / metabolism
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / genetics
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Neurons / drug effects
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Neurons / metabolism
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Potassium Channels / genetics
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Potassium Channels / metabolism*
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Pyrimidines / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Triazines / therapeutic use
Substances
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Excitatory Amino Acid Antagonists
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Hcn1 protein, mouse
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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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Neurofibromin 1
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Potassium Channels
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Pyrimidines
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Triazines
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ICI D2788
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Lamotrigine