P166 Leveraging neural modeling of channelopathies to elucidate neural mechanisms underlying neurodevelopmental disorders
Molly Leitner*1, Roman Baravalle1,James Chen1,Timothy Fenton3, Roy Ben-Shalom3, Salvador Dura-Bernal1,2
1Department of Physiology and Pharmacology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
2Center for Biomedical Imaging & Neuromodulation, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA
3Neurology Department, University of California Davis, Davis, CA, USA
*Email: molly.leitner@downstate.edu
Introduction
Neurodevelopmental disorders (NDDs), such as epilepsy, autism spectrum disorder, and developmental delays, present with considerable clinical variability and often impair social interactions, speech, and cognitive development. A key feature of these disorders is an imbalance in excitatory/inhibitory (E/I) input, which disrupts neuronal circuit function during development. Brain channelopathies, where neuronal ion channel activity is altered, provide an ideal model for studying E/I imbalance, as their effects can be directly linked to neuronal excitability. Ion channels are crucial in generating electrical activity in neurons, and disruptions to this activity are strongly associated with NDDs [1].
Methods
Studying channelopathies at the single-cell level is well-established, however, investigating the impact of specific channel mutations on neuronal circuits requires more complex approaches.By utilizing a previously developed primary motor cortex (M1) model built using NetPyNE and NEURON, we employ large-scale, highly detailed biophysical neuronal simulations to examine how channel mutations influence individual and network neuronal activity [2].
Results
These simulations offer a mechanistic understanding of how channelopathies contribute to E/I imbalance and the pathology of NDDs. Through the M1 cortical column simulation, we measure the effects of biophysical changes in ion channels on network excitability and neuronal firing patterns, providing insights into the pathophysiology of simulated channelopathies.
Discussion
This model not only serves as a tool for investigating specific channelopathy cases but also enables the exploration of pharmacological agents aimed at restoring E/I balance. Ultimately, this approach will enhance our understanding of targeted therapeutic strategies for alleviating disease symptoms and may uncover novel treatments with clinical potential.
Acknowledgements
This work was supported by the Hartwell Foundation through an Individual Biomedical Research Award. The authors gratefully acknowledge the foundation’s commitment to innovative pediatric research and its generous support of our project.
References
● Spratt PWE, Ben-Shalom R, Keeshen CM, Burke KJ Jr, Clarkson RL, Sanders SJ, Bender KJ. The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex. Neuron. 2019 Aug 21;103(4):673-685.e5. doi: 10.1016/j.neuron.2019.05.037.
● Dura-Bernal S, Neymotin SA, Suter BA, Dacre J, Moreira JVS, Urdapilleta E, Schiemann J, Duguid I, Shepherd GMG, Lytton WW. Multiscale model of primary motor cortex circuits predicts in vivo cell-type-specific, behavioral state-dependent dynamics. Cell Rep. 2023 Jun 27;42(6):112574. doi: 10.1016/j.celrep.2023.112574.
