Epileptiform activity induces distance-dependent alterations of the Ca²⁺ extrusion mechanism in the apical dendrites of subicular pyramidal neurons

Abstract

The cellular and molecular mechanisms that underlie acquired changes in Ca²⁺ dynamics of different neuronal compartments are important in the induction and maintenance of epileptiform activity. Simultaneous electrophysiology and Ca²⁺ imaging techniques were used to understand the basic properties of dendritic Ca²⁺ signaling in rat subicular pyramidal neurons during epileptiform activity. Distance-dependent changes in the Ca²⁺ decay kinetics locked to spontaneous epileptiform discharges and back-propagating action potentials were observed in the apical dendrites. A decrement in the mean Τ value of Ca²⁺ decay was observed in distal parts (95-110 μm) of the apical dendrites compared with proximal segments (30-45 μm) in in-vitro epileptic conditions but not in control. Pharmacological agents that block Ca²⁺ transporters, i.e. Na⁺/ Ca²⁺ exchangers (Benzamil), plasma membrane Ca²⁺-ATPase pumps (Calmidazolium) and smooth endoplasmic reticulum Ca²⁺-ATPase pumps (Thapsigargin), were applied locally to the proximal and distal part of the apical dendrites in both experimental conditions to understand the molecular aspects of the Ca²⁺ extrusion mechanisms. The relative contribution of Na⁺/Ca²⁺ exchangers in Ca²⁺ extrusion was higher in the distal apical dendrites in the in-vitro epileptic condition and this property modulated the excitability of the neuron in simulation. The Ca²⁺ homeostatic mechanisms that restore normal Ca²⁺ levels could play a major neuroprotective role in the distal dendrites that receive synaptic inputs.