Neuromodulation of synaptic plasticity at schaffer-collateral synapses on a hippocampal CA1 pyramidal neuron during theta oscillations: a computational modeling study

Abstract

Background and aim: Hippocampal CA1 pyramidal neurons receive excitatory synaptic inputs from entorhinal cortex (EC) and CA3 neurons, inhibitory synaptic inputs from many classes of interneurons, and can oscillate in a theta rhythm (4-10Hz). Synaptic plasticity varies across the theta cycle, from strong long-term potentiation (LTP) to long-term depression (LTD), corresponding to the memory encoding and retrieval cycles. Learning in hippocampus is also affected by cholinergic neuromodulation: acetylcholine (ACh) enhances long-term potentiation (LTP), increases neuron excitability, suppresses synaptic transmission (Hasselmo, Curr Opin Neurobiol, 2006), and its function is impaired in Alzheimer’s disease. We aim to analyze the modulatory effect of ACh on synaptic plasticity at Schaffer-collateral synapses in a CA1 network during theta oscillations. Materials and methods: We employ a multicompartmental model of CA1 pyramidal neuron embedded in a model of the CA1 pyramidal neuron microcircuit (Cutsuridis et al., Hippocampus, 2010; Saudargiene et al, Hippocampus 2015). The influence of ACh is modeled by reduction of potassium IA and IAHP current density and increase in maximal synaptic conductance of NMDAr channels. Results: Weak CA3 inputs paired with the EC inputs evoke large calcium transients and result in LTP at Schaffer-collateral synapses activated in encoding phase even when somatic spiking is inhibited by perisomatic basket cell activity. Weak CA3 inputs alone induce lower calcium transients and cause LTD. Neuromodulation enhances LTP or switches LTD to LTP. In retrieval phase, strong CA3 inputs alone induce lower calcium transients due to bistratified inhibition and cause LTD. Neuromodulation converts this LTD to LTP. Conclusions: The results imply that cholinergic neuromodulation plays an important role in synaptic plasticity and together with the spatio-temporal pattern of synaptic inputs defines the properti[...].