Effects of HCN2 Mutations on Dendritic Excitability and Synaptic Plasticity: A Computational Study. (15th December 2019)

• Record Type: Journal Article
• Authors: Thomas, Mitha; Ranjith, G.; Radhakrishnan, Ashalatha; Arun Anirudhan, V.
• Is Part Of: Neuroscience. Volume 423(2019)
• Page Start: 148
• Page End: 161
• Publication Date: 2019-12-15
• Subjects: HCN hyperpolarisation-activated cyclic nucleotide-gated -- NaF fast sodium -- CaT T-type calcium -- CaR R-type calcium -- KDR delayed rectifier potassium -- KA A-type potassium -- SK small conductance potassium -- AMPAR α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor -- NMDAR N-methyl-d-aspartate receptor -- SMT sliding modification threshold -- BCM Bienenstock–Cooper–Munro -- cAMP cyclic adenosine mono phosphate -- CNBD cyclic nucleotide binding domain -- SA sinoatrial -- CA cornu ammonis -- LTP long term potentiation -- LTD long term depression -- DNA deoxyribonucleic Acid -- NMODL NEURON Model Description Language -- GHK Goldman–Hodgkin–Katz -- HH Hodgkin–Huxley -- RMP resting membrane potential -- EK reverse potential of potassium -- ENa reverse potential of sodium -- Eh reverse potential of HCN current -- Elk reverse potential of leak component of HCN current -- PAMPAR AMPAR permeability -- PNMDAR NMDAR permeability -- g¯Na maximum conductance density of NaF -- g¯KDR maximum conductance density of KDR -- g¯KA maximum conductance density of KA -- g¯CaT maximum conductance density of CaT -- g¯CaR maximum conductance density of CaR -- g¯h maximum conductance density of HCN -- g¯SK maximum conductance density of SK -- WT wild type -- V1/2 half-maximal activation voltage -- AHP after-hyperpolarisation -- GABA gamma-amino butyric acid -- AED anti-epileptic drug; HCN channels -- epilepsy -- intrinsic excitability -- BCM theory -- metaplasticity -- sliding modification threshold; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2019.10.019
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: HCN2 mutations can induce changes in neuronal membrane input resistance and resting membrane potentials. Gain-of-function as well as loss-of-function mutations of HCN channels can result in hyperexcitable dendrites. A complex relationship connects I h and neuronal excitability, making the first modify the latter in complex ways. Abstract: Several reports of augmented hyperpolarisation-activated cyclic nucleotide-gated (HCN) currents in seizures have suggested a pro-convulsive identity for HCN channels. The mutations identified in one or more of the four HCN channel subunits are found to be contributing to different epileptic phenotypes. S126L, S632W, V246M and E515K are four different mutations affecting the HCN2 subunit and have been reported in febrile seizures and partial/generalised idiopathic epilepsies. From the visible outcomes in subjects with these mutations, it is evident that they must play important roles in altering dendritic excitability. Through this simulation study using NEURON, we created a three-compartmental, hippocampal CA1 pyramidal neuron synapse model expressing seven different ion channels (fast sodium (NaF), T-type calcium (CaT), R-type calcium (CaR), delayed rectifier potassium (KDR), A-type potassium (KA), small conductance potassium (SK), and HCN channels) and two glutamate receptors (AMPAR and NMDAR). We modelled an HCN2 channel and incorporated changes in it to obtain mutation kinetics. Their effects on excitability were studied by observing resting membrane potentials, input resistances and plasticity profiles for measuring the sliding modification threshold (SMT) of Bienenstock–Cooper–Munro (BCM) theory. Virtual knockouts of ion channels other than HCN were also performed to assess their role in altering excitability when they act alongside HCN2 mutations. Our results show that HCN2 mutations can potentially be a primary causative factor for excessive action potential firing through their effect on resting membrane potentials and input resistance.