Differential alterations of entorhinal versus CA3 impact on ventral CA1 pyramidal neurons in 5xFAD mice.

Abstract

Most hippocampal physiologic studies in Alzheimer disease (AD) have focused on memory circuit dysfunction in dorsal CA1. Ventral CA1 (vCA1) has received little attention, despite evidence supporting its increased susceptibility and its role in mood and affective symptoms, which play a prominent role in AD. We aimed to study the effect of amyloid pathology on circuit dysfunction in vCA1 using 5xFAD mice. We evaluated intrinsic excitability of vCA1 pyramidal neurons (PNs) as well as the impact of two distinct inputs onto their apical dendrite: entorhinal cortex (EC) input onto the distal compartment and CA3 inputs onto the proximal compartment. Acute ventral hippocampal slices were prepared from 12-14 month old 5xFAD and age-matched wild type (WT) mice. Whole cell patch clamp recordings were performed on vCA1 PNs. EC and CA3 input responses were elicited with extracellular stimulation of stratum lacunosum moleculare and stratum radiatum. We also addressed presynaptic function (paired pulse ratio), dendritic excitability (decay time constant of synaptic response), and intrinsic excitability (resting membrane potential, input resistance, sag ratio, firing rate). The EC stimulus-response curve reduced in 5xFAD vs. WT mice (n=6-10 PNs; p=0.0096) with a peak reduction of ∼33% (1.5mV vs. 1.0mV). In these same cells, the CA3 stimulus-response curve was also reduced (p<0.0001) but to a much larger extent of ∼67% at the peak (4.3mV vs. 1.4mV). The paired pulse ratio and response decay time constant were not affected with either input. Lastly, there were no statistically significant changes in intrinsic excitability measures. In 5xFAD mice, vCA1 PN circuit dysfunction is dominated by synaptic not intrinsic excitability changes. These changes are not in presynaptic function or postsynaptic ion currents, suggesting glutamate receptor changes or spine loss as alternative mechanisms. Moreover, these alterations are much more evident in CA3 versus EC input responses, perhaps driven by the inherent differences of the proximal and distal dendritic compartment. As such, with amyloidosis, vCA1 PN output shifts from being heavily dependent on CA3 input to being nearly equivalently dependent on EC input. These changes are important for understanding the circuit basis of mood and affect dysfunction in AD.