HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1.
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.
Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands.|ENCORE Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, The Netherlands.
A
A
Omrani
Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands.|ENCORE Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Pediatrics, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
T
T
van der Vaart
Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands.|ENCORE Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, The Netherlands.
E
E
Mientjes
Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands.|ENCORE Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, The Netherlands.
G M
GM
van Woerden
Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Physiology, Shahrekord University of Medical Sciences, Shahrekord, Iran.
M R
MR
Hojjati
Department of Molecular and Cellular Neurobiology, CNCR, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
K W
KW
Li
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
D H
DH
Gutmann
Department of Molecular Visual Plasticity, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands.
C N
CN
Levelt
Department of Molecular and Cellular Neurobiology, CNCR, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
A B
AB
Smit
Department of Neurobiology, Brain Research Institute, University of California Los Angeles, Los Angeles, CA, USA.
A J
AJ
Silva
ENCORE Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
S A
SA
Kushner
Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands.|ENCORE Center for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, The Netherlands.
Y
Y
Elgersma
D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism*; D000077213:Lamotrigine; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000150:complications* / Q000235:genetics; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014227:Triazines / Q000627:therapeutic use
D018691:Excitatory Amino Acid Antagonists; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D025542:Neurofibromin 1; D015221:Potassium Channels; D011743:Pyrimidines; D014227:Triazines; C082246:ICI D2788; D000077213:Lamotrigine