Computational Study of Dopamine Receptor and Calcium Channel Interactions in Layer II Stellate Cell Excitability

Authors: Chitaranjan Mahapatra, Andrew P. Davison

Presentation type: Poster at SNUFA 2024 online workshop (5-6 Nov 2024)

Abstract

MOTIVATION: Stellate cells in layer II of the medial entorhinal cortex play critical roles in memory, cognition, and perception, with their firing patterns regulated by subcellular calcium dynamics in the axon initial segment (AIS). Recent research suggests potential coupling between dopamine D2 receptors (D2R) and T-type Ca2+ channels as a key factor in this modulation. This study aims to investigate how this coupling influences resting membrane potential (RMP) and action potential (AP) plasticity in pathological conditions.

METHODS: Biophysical parameters for ion channels in the AIS of layer II stellate cells were adapted from existing models. Equations were developed to simulate D2R-mediated cAMP regulation, linked with T-type Ca2+ channel conductance using a modified Boltzmann equation. Simulations of RMP, APs, and T-type Ca2+ currents were performed using the NEURON platform under voltage clamp and current clamp conditions.

RESULTS AND DISCUSSION: Application of 10 µM dopamine agonist decreased AP threshold by 3 mV, reduced dV/dt by 1 mV/ms, and lowered RMP by 2 mV. AP frequency decreased from 6 to 4 spikes/s under 400 pA current. Reduced cAMP levels shifted the half-activation potential of T-type Ca2+ channels from –36 mV to –32 mV. Activation of D2R reduced window current, counterbalanced by a decrease in A-type K+ channel conductance. These findings suggest that cAMP antagonists and K+ channel agonists could be therapeutic alternatives for dopamine in pathological conditions, potentially improving spatial memory performance.

Keywords: Layer II Stellate cells, Dopamine receptor, T-type Ca2+ channel, Computational model