Figure 11. Model Schematics.

(A) Reconstructed morphology ported to NEURON simulation program, with somatic current injection site labeled. (B) Equivalent circuit diagram, with the reversal potentials for each channel indicated by E_X. The following currents were modeled using Ohmic drive and conductances in parallel with a membrane capacitance (C_M): a Na⁺ current (I_Na), L-type (I_CaL), R-type (I_CaR), and T-type (I_CaT) Ca²⁺ currents, two delayed rectifiers (I_Kv1 and I_Kv2), an A-type K⁺ current (I_A), an inward rectifying K⁺ current (I_KIR), a nonspecific Ca²⁺-activated current (I_CAN), a hyperpolarization-activated mixed cationic h-current (I_h), and a leak current (I_L). (C) Markov Model of the Na_V channel with an open state (O), a closed state (C), a short-term inactivated state (I1) and a long-term inactivated state (I2). See also Figure 11—figure supplement 1.

Figure 11—figure supplement 1. Old model in which the source of Ca²⁺ with privileged access to the nanodomain required to activated TRPM4 channels is IP₃R.

This model captures the responses seen with cholinergic activation in the experiments. (A) Simulated somatic recordings in control (low IP₃). (A1) Voltage traces and current ramp. (A2) Nanomolar Ca²⁺ concentration in outer shell beneath the cell membrane. (A3) The nanodomain Ca²⁺ concentration is not elevated with low levels of IP₃ that simulate control. (A4) There is negligible TRPM4 activation. B. Simulated somatic recordings in CCh (high IP₃). (B1) Voltage traces and current ramp. (B2) Nanomolar Ca²⁺ concentration in outer shell beneath the cell membrane is elevated due to increased spiking on the down-ramp. (B3) The nanodomain Ca²⁺ concentration reached micromolar concentrations with high levels of IP₃ that simulate application of CCh. (B4) TRPM4 is robustly activated. Black dashed line marks the end of the injected current ramp, highlighting that the return to baseline of Ca²⁺ and TRPM4 current lags behind injected current ramp. (C) Simulated somatic recordings in CCh (high IP₃) with no nanodomain. (C1) Voltage traces and current ramp. Note that more ramp current is required to achieve the same firing rates as were achieved in B1. (C2) Nanomolar Ca²⁺ concentration in outer shell beneath the cell membrane.( C3) No nanodomain. (C4) There is negligible TRPM4 activation. In A2 and C2, the red arrows point to when the [Ca²⁺] in the outer shell starts decreasing while the neuron keeps firing, as opposed to B2.