Altered intrinsic excitability impairs synaptic plasticityat Schaffer-collateral synapses on hippocampalCA1 pyramidal neuron in Alzheimer’s disease

Abstract

Long-term potentiation (LTP) and long-term depression(LTD), the ability of a synapse to enhance or weaken itsstrength, is believed to be a biological basis of learning andmemory. Hippocampal synaptic plasticity is modulated bythe alterations in neuronal intrinsic excitability. Intrinsicexcitability and synaptic plasticity are affected in Alzheimer’sdisease (AD), a neurodegenerative disorder, characterizedby progressive memory loss and cognitive dysfunction.In the early stage of AD, hippocampal learning impairmentis observed due to the accumulation of amyloid precursorprotein (APP) metabolite APP intracellular fragment(AICD) that modifies intrinsic excitability of hippocampalCA1 pyramidal neuron and disrupts synaptic plasticity (Sajikumaret al., 2014 Aug 19).In this study, we investigated the effect of altered intrinsicexcitability on synaptic plasticity in a hippocampal CA1pyramidal cell affected by AD using a computational modelingapproach. We used a detailed compartmental modelof a hippocampal CA1 pyramidal neuron (Cichon & Gan,2015 Apr) and included the influence of AICD by alteringthe small-conductance calcium-activated potassium channels(SK), L-type calcium channels, and contribution of theGluN2B-containing NMDA receptor (NMDAr). A modifiedNMDAr dependent voltage-based synaptic plasticity model(Sezener et al., 2021) was used to analyse synaptic plasticitychanges at clustered Schaffer collateral synapses. Eachcluster contained 50 synapses distributed along the dendriticbranches with densities in a range of 0.05 to 1.0 synapse/μm. The synapses were stimulated with 1 Hz for 900 s toinduce LTD and 2 bursts of 100 Hz for 1 s, separated by2 s window for LTP (Sajikumar et al., 2014 Aug 19). Theresults show that altered neuronal intrinsic excitability dueto the increased AICD production disrupts LTP leaving LTD intact. Elevated AICD levels enhance NMDAr expressionand lead to SK channel overactivation, thus reducing neuronsensitivity to the incoming presynaptic inputs for high frequencyLTP induction protocol. Contrary, neuron adequatelyresponds to low frequency stimulation and maintains LTD.Partial blockade of NMDAr restores normal SK channelfunction and rescues LTP. These findings provide insightsinto the pathological dynamical effects of AICD on NMDAr,SK channel properties, the resulting neuronal intrinsic excitabilityand impaired synaptic plasticity.