Scaling and Benchmarking an Evolutionary Algorithm for Constructing Biophysical Neuronal Models

Ladd, Alexander; Kim, Kyung Geun; Balewski, J.; Bouchard, Kristofer E.; Ben-Shalom, Roy

doi:10.3389/fninf.2022.882552

Cited by 2 publications

(3 citation statements)

References 72 publications

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“…The optimization of parameters for the compartmental model containing HMM Na V 1.6 channels was conducted using an evolutionary algorithm facilitated by BluePyOpt [32], which was adapted to the computational infrastructure of the National Energy Research Computing Center [33]. This process ensured the functional equivalence of the HMM model parameters to those of the established HH model before incorporating any Na V 1.6 mutations.…”

Section: Methodsmentioning

confidence: 99%

“…Here, To further explore the effects of Na V 1.6 G1625R expression, we modified a wellestablished computational model of a layer V cortical pyramidal cell (25)(26)(27)(28)(29)(30). We optimized a hidden Markov model (HMM) to represent Na V 1.6 channels using an in-house evolutionary algorithm similar to previous studies (31,32). The HMM model parameters were fit to recapitulate the kinetics of the Hodgkin-Huxley (HH) formalism used originally in the model.…”

Section: Computational Modeling Of Na V 16 G1625r Effect On Neuronal ...mentioning

confidence: 99%

“…Computing Center [33]. This process ensured the functional equivalence of the HMM model parameters to those of the established HH model before incorporating any Na V 1.6 mutations.…”

Section: Computational Modelingmentioning

confidence: 99%

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Complex biophysical changes and reduced neuronal firing in anSCN8Avariant associated with developmental delay and epilepsy

Quinn,

Zhang,

Fenton

et al. 2023

Preprint

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SummaryBackgroundMutations in theSCN8Agene, encoding the voltage-gated sodium channel NaV1.6, lead to various neurodevelopmental disorders. TheSCN8Ap.(Gly1625Arg) mutation (NaV1.6G1625R) was identified in a patient diagnosed with developmental epileptic encephalopathy (DEE), presenting with moderate epilepsy and severe developmental delay.MethodsWe performed biophysical and neurophysiological characterizations of NaV1.6G1625Rin Neuro-2a cells and cultured hippocampal neurons, followed by computational modeling to determine the impact of its heterozygous expression on cortical neuron function.FindingsVoltage-clamp analyses of NaV1.6G1625Rdemonstrated a heterogeneous mixture of gain-and loss-of-function properties, including reduced current amplitudes, a marked increase in the time constant of fast voltage-dependent inactivation and a depolarizing shift in the voltage dependence of inactivation. Recordings in transfected cultured neurons showed that these intricate biophysical properties had a minor effect on neuronal excitability when firing relayed on both endogenous and transfected NaVchannels. Conversely, there was a marked reduction in the number of action potentials when firing was driven by the transfected mutant NaV1.6 channels. Computational modeling of mature cortical neurons further revealed a mild reduction in neuronal firing when mimicking the patients’ heterozygous NaV1.6G1625Rexpression. Structural modeling of NaV1.6G1625Rand a double-mutant cycle analysis suggested the possible formation of pathophysiologically-relevant cation-π interaction between R1625 and F1588, affecting the voltage dependence of inactivation.InterpretationOur analyses demonstrate a complex combination of gain and loss-of-function changes resulting in an overall mild reduction in neuronal firing, related to a perturbed interaction network within the voltage sensor domain.FundingISF, DFG, BMBF, The Hartwell Foundation, ICRF, ISCAResearch in contextEvidence before this studyMutations in theSCN8Agene, encoding the voltage-gated sodium channel NaV1.6, result in multiple neurodevelopmental syndromes ranging from benign epilepsy to developmental delay without epilepsy or developmental epileptic encephalopathy (DEE). Recent studies established that most DEE-causingSCN8Amutations result in a gain of function effect. However, severalSCN8Amutations that diverge from this pattern were described.Added value of this studyWe performed a multi-tiered study of theSCN8Ap.(Gly1625Arg) variant (NaV1.6G1625R), identified in a patient with atypical DEE presentation, featuring moderate epilepsy that is well controlled by the sodium channel blocker Oxcarbazepine, along with profound stagnated developmental delay.This variant is positioned within the S4 segment of domain IV, a critical region for NaV1.6 function, where pathogenic variants were shown to cause either a loss or gain of channel function, but often with mixed biophysical alterations.Our biophysical characterization of NaV1.6G1625Rin Neuro-2a cells demonstrated complex gain-and loss-of-function properties, cumulating to reduced firing in cultured hippocampal neurons and computational modeling of mature cortical neurons, demonstrating an overall loss-of-function effect.Implications of all the available evidenceOur results indicate the necessity for combined biophysical and neuronal characterization of individualSCN8Avariants, especially those presenting with complex biophysical changes or atypical clinical presentation. Moreover, while sodium channel blockers are the recommended treatment forSCN8Avariants associated with gain-of-function, additional considerations may be needed for DEE-causing variants that are associated with mild loss-of-function.

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Section: Methodsmentioning

confidence: 99%

Section: Computational Modeling Of Na V 16 G1625r Effect On Neuronal ...mentioning

confidence: 99%

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Complex biophysical changes and reduced neuronal firing in anSCN8Avariant associated with developmental delay and epilepsy

Quinn,

Zhang,

Fenton

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Complex biophysical changes and reduced neuronal firing in an SCN8A variant associated with developmental delay and epilepsy

Quinn,

Zhang,

Fenton

et al. 2024

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Scaling and Benchmarking an Evolutionary Algorithm for Constructing Biophysical Neuronal Models

Cited by 2 publications

References 72 publications

Complex biophysical changes and reduced neuronal firing in anSCN8Avariant associated with developmental delay and epilepsy

Complex biophysical changes and reduced neuronal firing in anSCN8Avariant associated with developmental delay and epilepsy

Complex biophysical changes and reduced neuronal firing in an SCN8A variant associated with developmental delay and epilepsy

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