Calcium-dependent subthreshold fluctuations in membrane voltage; a modeling study

Membrane potential noise plays multiple functional roles in the nervous system, as described in the review by Faisal et al[1]. Calcium-dependent potassium (K_Ca) channels are ion channels whose conductance depends on intracellular calcium concentration. Previous work by Diba et al suggests that such channels play a central role in subthreshold voltage noise [2]. While most channels generate noise through their inherent thermal fluctuations, we hypothesize that K_Ca channels also generate low-frequency subthreshold oscillations by transmitting stochastic fluctuations in intracellular calcium.

Methods

We have produced a stochastic computer model that incorporates K_Ca channels and calcium dynamics into a CA3 pyramidal neuron, which is based on the biophysically realistic Traub model [3]. To introduce channel noise, we replaced all Hodgkin-Huxley (HH) channels with equivalent Markov models [4]. There is also an intracellular calcium pool, with Ca²⁺ levels that vary stochastically due to influx through Markovian calcium channels.

Results

Preliminary simulation results show that, for the default parameters used by Traub, there is anti-correlation between intracellular calcium and membrane voltage (Figure 1); this suggests intracellular calcium fluctuations may partially drive low-frequency voltage noise. Additional modeling has implicated the Ca²⁺-dependent afterhyperpolarization current (I_AHP) as the primary linkage between these two signals. Power spectrum analysis suggests that the contribution of intracellular calcium fluctuations is dominant at low frequencies, below the natural cutoff for I_AHP noise (Figure 2). We believe that this linkage between membrane potential noise and intracellular calcium could regulate many of the well-documented roles of noise in the nervous system [1].

Figure 1

Relationship between intracellular calcium and membrane voltage. Intracellular calcium (blue, arb units) is inverted and scaled to show anti-correlation with membrane voltage (green). (Correlation coefficient -56.4%, Vm phase lag ~600ms, Traub model default parameters.)

Figure 2

Power spectral density for stochastic I _AHP current Black trace is simulation under default settings. Red trace shows the effects of clamping intracellular calcium, which reduces low-frequency power. Green trace shows the I_AHP current when inherent thermal fluctuations are removed by switching channel dynamics from Markov to HH. The crossover of these two signals suggests that intracellular calcium fluctuations can contribute to low-frequency voltage noise.