Medial prefrontal cortex pyramidal neurons exhibit functional defects during early stage of Alzheimer’s disease in 3xTg‐AD mice

Abstract

The brain regions that show early increase of beta-amyloid (Aβ) in Alzheimer's disease (AD) overlap with the default mode network (DMN) (Palmqvist, S. et. al., 2017), which comprises, but is not limited to, the medial prefrontal cortex (mPFC), a key regulator of neurocognition (Zott, B. et al., 2018). DMN is active during mental processes that don't require attention, but it is deactivated when undertaking neurocognitive tasks (Zott, B. et al., 2018). However, such DMN deactivation is impaired in AD, often preceding formation of the Aβ plaque and onset of clinical symptoms (Chhatwal, J. P. et al., 2013; Sheline, Y. I. et al., 2010). Previous studies suggest that neuronal hyperexcitability is responsible for increased DMN vulnerability to Aβ deposition (Bero, A. W. et al., 2011; Li, X. et al., 2013). But whether and how mPFC neuronal function are altered in the early stages of AD is unknown and has not been studied.In this study, we used young 3xTg-AD mice (3-5 months of age) to mimic the early stages of AD before the formation of cortical Aβ plaques. Patch-clamp electrophysiology was applied to assess functional activity of mPFC pyramidal neurons in brain slices. Action potentials were evoked by depolarizing currents and spontaneous excitatory postsynaptic currents (sEPSCs) were assessed in Mg2+ -free bath with holding potential of -70mV. Ca2+ spikes (indicating Ca2+ influx through voltage-gated Ca2+ channels) were evoked by membrane depolarization with blockade of voltage-gated Na+ /K+ channels.We found that mPFC pyramidal neurons in young 3xTg-AD mice showed significantly increased firing, associated with depolarized resting membrane potential, decreased rheobase, increased input resistance, and reduced firing threshold. We also found that the frequency of sEPSCs was significantly increased. Meanwhile, Ca2+ spikes showed a trend of increase in their duration/area (a larger sample size is needed to confirm this finding) in mPFC neurons.Collectively, these novel findings demonstrate that the neuronal excitability and excitatory neurotransmission are aberrantly increased in the young mPFC during the early stages of AD preceding Aβ plaque formation. Whether such mPFC neuronal dysfunction could contribute to Aβ plaque accumulation is currently unknown and requires further investigation.