Calcium regulation of HCN channels supports persistent activity in a multiscale model of neocortex

Neuronal persistent activity has been primarily assessed in terms of electrical mechanisms, without attention to the complex array of molecular events that also control cell excitability. We developed a multiscale neocortical model proceeding from the molecular to the network level to assess the contributions of calcium (Ca²⁺) regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in providing additional and complementary support of continuing activation in the network. The network contained 776 compartmental neurons arranged in the cortical layers, connected using synapses containing AMPA/NMDA/GABA_A/GABA_B receptors. Metabotropic glutamate receptors (mGluR) produced inositol triphosphate (IP₃) which caused the release of Ca²⁺ from endoplasmic reticulum (ER) stores, with reuptake by sarco/ER Ca²⁺-ATP-ase pumps (SERCA), and influence on HCN channels. Stimulus-induced depolarization led to Ca²⁺ influx via NMDA and voltage-gated Ca²⁺ channels (VGCCs). After a delay, mGluR activation led to ER Ca²⁺ release via IP₃ receptors. These factors increased HCN channel conductance and produced firing lasting for ~1min. The model displayed inter-scale synergies among synaptic weights, excitation/inhibition balance, firing rates, membrane depolarization, Ca²⁺ levels, regulation of HCN channels, and induction of persistent activity. The interaction between inhibition and Ca²⁺ at the HCN channel nexus determined a limited range of inhibition strengths for which intracellular Ca²⁺ could prepare population-specific persistent activity. Interactions between metabotropic and ionotropic inputs to the neuron demonstrated how multiple pathways could contribute in a complementary manner to persistent activity. Such redundancy and complementarity via multiple pathways is a critical feature of biological systems. Mediation of activation at different time scales, and through different pathways, would be expected to protect against disruption, in this case providing stability for persistent activity.