Linkevičius, Domas

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[...].

Background and aim: Alzheimer’s disease (AD) is steadily growing to be the leading cause of death in the 1st world countries, with incidence of dementia doubling every 10 years after the age of 60 and almost 90% suffering from it at 90 years of age. The two hallmark features of AD are beta-amyloid (Aβ) accumulation and Tau protein aggregates in the brain. Aβ increase in the brain has an effect on intra/extracellular calcium homeostasis and leads to progressive dendritic atrophy, synaptic and neuronal loss. The mechanism by which Aβ mediates cell death and initiates degenerative processes of AD continues to elude the scientific community to this day. The aim of the study is to analyze the effect of Aβ accumulation on dendritic excitability and synaptic plasticity in CA1 pyramidal neurons using computational modeling methodology. Materials and methods: We use a multicompartmental model of CA1 pyramidal neuron (Poirazi et al., Neuron, 2003) and synaptic plasticity model (Graupner and Brunel, PNAS, 2012) to investigate the influence of Aβ accumulation on intracellular calcium dynamics and synaptic plasticity at excitatory synapses in CA1 pyramidal neurons. The influence of pathological Aβ changes is modeled by blocking A-type K+ channels (IA) in pyramidal cell dendrites and increasing NMDA glutamate receptor maximal conductance in Schaffer collateral synapses. Results: Aβ accumulation leads to the enhanced CA1 pyramidal neuron dendritic excitability, increased amplitude of back-propagating action potentials, higher intracellular calcium transients and promotes long-term potentiation. Conclusions: The results show that prior to cell death Aβ accumulation alters properties of synaptic plasticity and learning in hippocampal CA1 pyramidal neurons.