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bioRxiv · 10.64898/2025.12.01.691675

Anterior thalamic nucleus inputs to the retrosplenial cortex are unperturbed in the hAPP-J20 mouse model of Alzheimer's disease

Margetts-Smith, G.·Andrianova, L.·Kohli, S.·Randall, A. D.·Aggleton, J.·Witton, J.·Craig, M.
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Abstract

Alzheimers disease (AD) is a neurodegenerative condition characterised by progressive loss of memory and general decline in cognitive function. Although research has traditionally focused on the hippocampus and entorhinal cortex, other regions important for memory and spatial navigation, such as the anterior thalamic nuclei (ATN) and retrosplenial cortex (RSC), are also affected. The RSC is an important brain region for both memory and spatial navigation, and displays dysfunction in humans during prodromal phases of AD. The ATN provide a major input to RSC, with loss of this input to RSC causing a dramatic reduction in the expression of the immediate early gene product c-Fos. The ATN to RSC connection may thus present a new target for therapeutic intervention in AD. Here, we set out to determine whether AD-like pathology perturbed projections from ATN to RSC using the hAPP-J20 amyloidopathy mouse model, using optogenetic activation of thalamic inputs combined with ex vivo patch clamp electrophysiology. We found that RSC displayed an age-dependent decline in basal c-Fos activity, with no additional effect of amyloid pathology on c-Fos expression. At all time points (3, 6 and 9 months) measured, we found no evidence of impairments in the synaptic strength or efficacy of the ATN projections to either granular or dysgranular subdivisions of RSC. We conclude that, in the hAPP-J20 mouse model, this pathway is unaffected by amyloid-{beta} overexpression.

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Margetts-Smith, G., Andrianova, L., Kohli, S., Randall, A. D., Aggleton, J., Witton, J., Craig, M.. 2025-12-03. Anterior thalamic nucleus inputs to the retrosplenial cortex are unperturbed in the hAPP-J20 mouse model of Alzheimer's disease. https://doi.org/10.64898/2025.12.01.691675

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