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.

Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

“…Treatment with the HCN channel agonist lamotrigine during adulthood rescued the cognitive deficits in two different Nf1 mouse models, thereby establishing an important function of HCN channels in mediating the NF1 phenotype. In contrast, HCN function is unaffected in HRas G12V/G12V mice 25 .…”

“…Therefore, in order to investigate if a similar mechanism might be present in HRas G12V/G12V mice, we recorded spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in the presence of depolarizing levels of extracellular potassium (increased from 2.5 to 12.5 mM KCl), as previously shown for Nf1 mice 24, 25 . As expected, high extracellular potassium (12.5 mM) resulted in a significantly increased frequency of mIPSCs in both HRas G12V/G12V and WT mice (frequency: F 1,49  = 22.28, P  < 0.05, amplitude: F 1,49  = 1.21, P  = 0.28; Fig.…”

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders

“…This drug is an agonist of the hyperpolarization-activated, cyclic-nucleotide-gated channel 1 (HCN1) that is compromised predominantly in inhibitory interneurons of an animal model of the disorder. Lamotrigine has been demonstrated to correct the electrophysiological and the cognitive deficits in NF1 knockout mice (Omrani et al, 2015).…”

Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders

“…Recently, Omrani and colleagues showed that Nf1 mutants with the specific deletion of exon 9a recapitulate the phenotypes of the Nf1 +/-mice, including spatial learning and memory deficits in the water maze, increased GABAergic inhibitory synaptic transmission, and impaired hippocampal LTP (Omrani, van der Vaart, Mientjes, van Woerden, Hojjati, Li et al, 2015). In addition, Omrani et al identified hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) as a novel interacting partner of NF1 and showed that hyperpolarization-activated cation current was reduced selectively in parvalbumin (PV)-expressing inhibitory neurons in Nf1 9a-/9a-mice (Omrani et al, 2015). Moreover, augmenting the HCN current by lamotrigine treatment rescued the electrophysiological and behavioral deficits in both Nf1 9a-/9a-and Nf1 -/-mice (Omrani et al, 2015).…”

“…In addition, Omrani et al identified hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) as a novel interacting partner of NF1 and showed that hyperpolarization-activated cation current was reduced selectively in parvalbumin (PV)-expressing inhibitory neurons in Nf1 9a-/9a-mice (Omrani et al, 2015). Moreover, augmenting the HCN current by lamotrigine treatment rescued the electrophysiological and behavioral deficits in both Nf1 9a-/9a-and Nf1 -/-mice (Omrani et al, 2015). However, decreases in HCN1-current in Nf1 9a-/9a-mice might be independent from the upregulation of RAS-MAPK signaling.…”