Extended Data Figure 8: Simulation of LHb neurons incorporating T-VSCCs and NMDAR channels. | Nature

Extended Data Figure 8: Simulation of LHb neurons incorporating T-VSCCs and NMDAR channels.

From: Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

Extended Data Figure 8

a, Scheme of a single compartment model of an LHb neuron (see Methods). b, The contribution of NMDAR current INMDAR and T-VSCC current IT during bursts derived from simulation. c, RMP-dependent firing mode of the LHb model neuron. Spikes in bursting mode are shown in blue. Spikes in tonic and silent firing mode are shown in black. d, The correlation between RMPs and intra-burst frequencies of the LHb model neuron. e, f, Example trace (left) and statistics (right) showing in silico effects of ketamine (set NMDAR conductance gNMDAR = 0, e) or mibefradil (gT-VSCC = 0, f) on spontaneous bursts in the LHb model neuron. The bursting probability was evaluated across ten independent trials with simulated synaptic inputs. Note that in silico knockout of NMDAR or T-VSCC current from the model abolished the bursts, which matched experimental observations (Fig. 3a, d, 4a). g, h, Example trace (left) and statistics (right) showing in silico effects of NBQX (gAMPAR = 0, g) or AMPA (gAMPAR increased from 8 to 15 μS cm−2, h) on spontaneous bursts in the LHb model neuron. n = 10 simulations (eh). i, An example trace summarizing the ionic components and channel mechanisms involved in LHb bursting: hyperpolarization of neurons to membrane potentials negative to −55 mV slowly de-inactivates T-VSCC. IT continues to grow as the de-inactivated T-VSCCs increase, leading to a transient Ca2+ plateau potential. The Ca2+ plateau helps remove the magnesium blockade of NMDARs while T-VSCC inactivates rapidly during the depolarization. After the Ca2+ plateau reaches approximately −45 mV, INMDA dominates the driving force to further depolarize RMP to the threshold for Na spike generation. As RMP falls back to below −55 mV it de-inactivates IT and results in the intrinsic propensity of LHb neurons to generate the next cycle of bursting. Data are mean ± s.e.m.; ****P < 0.0001. Two-tailed paired t-test.

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