L-type CA2+ channel mediated CA2+ transient discriminates different firing patterns in hippocampal CA1 neurons : a modeling study

Evidence suggests an important role for L-type voltage sensitive Ca + channels (VSCCs) in activating immediate early genes (Murphy et al. 1991). To understand how L-type VSCCs regulate somatic and nuclear Ca2 + dynamics in response to different synaptic bursting waveforms that might be associated with unique forms of plasticity, we have modeled hippocampal CA1 neuron electrophysiology and intracellular Ca2+ dynamics. The model reproduces most of the eletrophysiological properties of hippocampal CA1 neurons, such as bursting vs. nonbursting behavior, AP frequency accommodation and AP back propagation. We examined Ca²⁺ influx through L-type VSCCs, and the resulting intracellular Ca²⁺ transient in response to simulated waveforms obtained with different presynaptic firing frequencies, active conductances and synaptic conductances. Simulation results suggest that L-type VSCCs prefer synaptic stimuli and conditions that result in a high depolarization plateau over other types of waveforms including repetitive APs, subthreshold EPSPs, or bursting firing. It was found that low activation potential and slow activation rate of L-type VSCCs contribute to the selective response of L-type VSCCs to firing patterns. Pharmacological experiments and simulation results suggest an important role of intracellular Ca²⁺ stores in nuclear Ca²⁺ elevation in response to either single AP or tetanic synaptic stimulus. Moreover, previous studies in muscle suggest a specific spatial relationship between the L-type VSCCs and the ryanodine receptor. Therefore, we sought to determine whether a similar coupling between Ca²⁺ channels and stores would facilitate Ca²⁺-induced Ca²⁺ release (CICR) action. Moving the Ca²⁺ stores away from the Ca²⁺ channels (from 50 nm to 2 μm) resulted in a large reduction in the elevation of Ca²⁺ transient.Medicine, Faculty ofGraduat