P149 Ion Channel Contributions to Spike Timing Precision in Computational Models of CA1 Pyramidal Neurons: Implications for Channelopathies
Anal Kumar*1, Upinder S. Bhalla1
1National Centre for Biological Science, Tata Institute of Fundamental Research, Bangalore, India
*Email:analkumar@ncbs.res.in
Introduction
Precise neuronal spike timing is essential for encoding [1,2], phase coding [3,4], and spike-timing-dependent plasticity (STDP) [5,6]. Disruptions in spike timing precision (SpTP) are linked to disorders such as auditory processing disorder [7] and autism spectrum disorder (ASD) [8,9]. These conditions are also associated with channelopathies [8], yet the specific contributions of different ion channels to SpTP remain unclear. In this study, we use computational models of CA1 pyramidal neurons to systematically examine how ion channel overexpression and underexpression affect SpTP, providing insights into disease mechanisms and potential therapeutic targets.
Methods
We constructed data-driven, conductance-based models of CA1 pyramidal neurons, incorporating realistic electrotonic, passive, and active features based on experimental recordings. Twelve ion channel subtypes were included, with kinetics derived from prior studies. To evaluate SpTP, we analyzed the coefficient of variation of inter-spike intervals and jitter slope across multiple trials of tonic 150 pA current injections. Gaussian noise was added to these current injections to simulate physiological noise. To determine the impact of early vs late activating ion channels on SpTP, we assessed SpTP separately for initial and later spikes in the spike train.
Results
Due to heterogeneity in the Gbar of ion channels across models, individual models exhibited variable effects of Gbar on SpTP. However, some global trends emerged:
● Initial spikes in the action potential train: SpTP negatively correlated with HCN and persistent sodium (Na_P) channels, while Kv3.1 showed a positive correlation. Transient sodium (Na_T) channels exhibited a non-monotonic relationship.
● Later spikes in the action potential train: SpTP negatively correlated with Na_P, whereas Kv3.1, K_SK, K_BK, and K_P showed a positive correlation.
Other channels, including K_P, K_T, K_M, K_D, and calcium channels (LVA, HVA), showed no significant impact on SpTP across trials.
Discussion
Previous studies have reported increased K_SK currents and reduced SpTP of later spikes in Fragile X Syndrome (FXS) [8]. Our findings corroborate this by demonstrating a positive correlation between K_SK Gbar and SpTP of later spikes, suggesting that K_SK upregulation may contribute to impaired temporal precision in FXS. Additionally, our study identifies potential therapeutic targets, such as Na_P channel blockade, which may help counteract the SpTP deficits observed in FXS. Further analysis of these models will help uncover the underlying mechanisms driving these correlations, shedding light on the role of ion channel dysfunction in neurodevelopmental disorders.
Acknowledgements
We thank NCBS, TIFR and Department of Atomic Energy, Government of India, under project identification No. RTI 4006 for funding. Special thanks to Dr. Deepanjali Dwivedi and Anzal KS for the raw experimental recordings. Thanks to NCBS animal house, Imaging facility, super computing facility at NCBS and members of Bhalla Lab.
References
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