Neuronal network bump attractors augmented by calcium up-regulation of Ih in a multiscale computer model of prefrontal cortex

Prefrontal cortex (PFC) is thought to be a site of short term memory based on persistent neuronal activity. Previous models have focused on the role of network connectivity via excitatory interconnections in maintaining activation to represent memory through bump attractors. We extended this model by taking account of roles of subcellular and cellular dynamics. A multiscale NEURON model was used to study dynamics across molecular, cellular and network scales. We focused on the role of calcium influence, via calcium-induced calcium release from endoplasmic reticulum (ER), on the hyperpolarization-activated cyclic-nucleotide gated (HCN) channels that produce Ih. This release was influenced by the network through the influence of metabotropic glutamate receptors (mGLUR) in excitatory neuron dendrites which produced IP3 through a G-protein mediation. The network itself was represented by 776 multicompartmental excitatory and inhibitory neurons arranged in the canonical cortical layers, and connected via metabotropic and ionotropic receptors (AMPA/NMDA, GABAA/GABAB). The network enabled individual neurons to maintain tonic NMDA synaptic activation to maintain sustained firing via mutual activation after a strong, brief excitatory stimulation, the classical bump attractor model of Wang et al (J Neurosci 19: 9587,1999). Activity was further augmented through cellular mechanisms, with higher availability of Ca up-regulating Ih, given preceding inhibitory-activation of Ih in the individual neuron through tonic bombardment of GABAA. GABAA therefore played a dual role – preparing a population for greater augmentation through activation of Ih and also suppressing non-selected cells during the period of bump activation. Glutamatergic activation also played a dual role: metabotropically preparing cells by allowing higher ER storage of Ca prior to stimulation, and ionotropically maintaining activation during the bump. The interactions between the metabotropic and ionotropic inputs to the neuron demonstrated how multiple pathways could contribute in a complementary manner to persistent activity. The network showed a complex interdependence between synaptic weights, excitation/inhibition balance, firing rates, membrane depolarization, Ca levels, regulation of HCN, and induction of persistent activity. The ability to mediate activation at different time scales, and through different pathways, would be expected to protect against disruption, in this case providing stability for working memory.