Synaptic Remodeling in Alzheimer’s Disease Alters the Input-Output Properties of Pyramidal Neurons

Document Type

Article

Publication Date

2025

Keywords

JMG

Abstract

Alzheimer's disease (AD), the most common form of dementia, is marked by progressive declines in cognitive function and is associated with the gradual loss of synaptic connectivity within neuronal circuits. The core function performed by neurons is the transformation of synaptic input to the dendrites into action potentials in the axon. Precisely how the loss of connectivity in AD affects these computations is poorly understood. Here, I use a computational model of a reconstructed hippocampal CA1 pyramidal cell to uncover how synapse loss impacts computations. The model, developed in the NEURON environment, simulates excitatory synapses to drive dendritic and somatic excitatory postsynaptic potentials. The model was adapted to reflect two changes found in AD mouse models: first, the widespread loss of synapses across the dendritic arbor, and second, the more focal loss of synapses at amyloid plaques adjacent to portions of dendrites. Through this approach, I show that spine loss causes dendritic branches to be more excitable due to increased input resistance, and that plaque-induced shifts in the spatial distribution of synapses can lead to both hypo- and hyperexcitable states within a single dendritic branch. Understanding how dendritic spine loss impacts cell excitability may prove valuable in directly linking how changes at the synapse alter the computational properties of neurons, possibly informing new strategies to address synaptic disconnection in AD progression.

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