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bioRxiv · 10.1101/2021.01.14.426651

ApoE4 attenuates cortical neuronal activity and impairs memory in young apoE4 rats

Har-Paz, I.·Arieli, E.·Moran, A.
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Abstract

The E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD related neuropathology. Understanding these primary dysfunctions is vital for early detection of AD and the development of therapeutic strategies for it. Recently we have shown impaired extra-hippocampal memory in young apoE4 mice - a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we test the hypothesis that these early structural deficits impact learning via changes in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 and wildtype rats, before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young apoE4 rats showed impaired CTA learning, consistent with our previous results in apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Single neuron and ensemble analyses of taste coding demonstrated that apoE4 neurons could be used to correctly classify tastes, but were unable to undergo plasticity to support learning. Our results suggest that apoE4 impacts brain excitability and plasticity early in life and may act as an initiator for later AD pathologies. Significant statementThe ApoE4 allele is the strongest genetic risk-factor for late-onset Alzheimers disease (AD), yet the link between apoE4 and AD is still unclear. Recent molecular and in-vitro studies suggest that apoE4 interferes with normal brain functions decades before the development of its related AD neuropathology. Here we recorded the activity of cortical neurons from young apoE4 rats during extra-hippocampal learning to study early apoE4 neuronal activity abnormalities, and their effects over coding capacities. We show that apoE4 drastically reduces basal and stimuli-evoked cortical activity in both excitatory and inhibitory neurons. The apoE4-induced activity attenuation did not prevent coding of stimuli identity and valence, but impaired capacity to undergo activity changes to support learning. Our findings support the hypothesis that apoE4 interfere with normal neuronal plasticity early in life; a deficit that may lead to late-onset AD development.

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Har-Paz, I., Arieli, E., Moran, A.. 2021-01-14. ApoE4 attenuates cortical neuronal activity and impairs memory in young apoE4 rats. https://doi.org/10.1101/2021.01.14.426651

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