Implications of long-range Mossy Cell signaling and connectivity in AD

Abstract
Alzheimer’s Disease (AD) has been identified as one of the highest priority neurobiological diseases in need of
research advancement, due to the progressive memory and emotional impairments inflicted on patients, and the
excessive burden for caregivers and families. Due to the continued lack of effective preventative treatments for
AD, it is imperative to identify ways to remediate the cognitive and affective impairments associated with the
disease, and it appears that a more synaptic and circuity focused approach may be necessary. The hippocampus
is one of the earliest regions in human and animal models to present with AD pathology and synaptic disfunction,
and it has established roles in both memory and emotional regulation. The dentate gyrus (DG), in particular,
undergoes many important circuitry and excitability changes in human cases of AD. As the first stop in the tri-
synaptic loop, DG has significant control over downstream activation of the CA3 and CA1 regions of the
hippocampus. Furthermore, since CA1 and subiculum project to many other structures throughout the brain,
important for memory consolidation and animal behavior, activity balance in the DG may impart brain-wide
functional connectivity changes under pathological conditions. Our previous research found that glutamatergic
Mossy Cells (MCs) in the DG have the unique capability to recruit either excitatory or inhibitory neurons
depending on the extent of MC activation. More recently, it has been discovered that MCs play a much more
significant role in hippocampal circuitry than previously thought, as these cells have unique anatomical projection
patterns that not only cross to the contralateral hemisphere, but also project longitudinally, along the entire
dorsal-ventral axis of the hippocampus. Our preliminary data acquired from the 5xFAD rodent model of AD has
identified a specific decrease in activity states of the dorsal population of MCs by 4.5 months of age, and a loss
in overall DG granule cell activity. Because of the unique anatomical characteristics of hippocampal MCs, and
due to the potential of dorsal MCs to regulate activity of DG granule cells throughout the hippocampus, we
postulate that loss of dorsal MC signaling is one of the key circuit deficiencies contributing to cognitive and
affective deficiencies in AD. By utilizing activity-dependent stimulation of dorsally targeted populations of MCs,
we aim to characterize the breakdown of excitatory and inhibitory control throughout the different regions of the
diseased hippocampus. We will use a combination of in vivo calcium imaging, chemogenetic stimulation of dorsal
MCs, small animal behavioral analysis, and awake small-animal fMRI scanning in mouse models of AD to
examine the effect MCs have on hippocampal activity and functional connectivity throughout the brain.
Identification of discrete network components with the potential to compensate for improper excitatory/inhibitory
balance and connectivity will greatly inform on the potential for circuity-based interventions to address the
cognitive and affective impairments of AD.

Grant Number: 1R21AG091124-01A1
NIH Institute/Center: NIH
Principal Investigator: BRENT ASRICAN