Voltage Imaging of Astrocyte-Neuron Interactions

Tufts University Boston, Boston MA

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT. Astrocytes control neurotransmission, contribute to a robust blood-brain-barrier (BBB), and metabolically support neuronal activity. In Alzheimer’s Disease (AD), astrocytes become reactive near A plaques, contribute to neuroinflammation, and contribute to synaptic and circuit abnormalities. The role that astrocytes play in controlling synaptic excitation by removing glutamate from the extracellular space is particularly intriguing in AD. Astrocytes express high levels of excitatory amino acid transporters (EAATs), including GLT1 and GLAST, in their peripheral processes that bind and remove extracellular glutamate to limit synaptic excitation. EAATs, as well as other astrocyte proteins, are known to be decreased late in AD progression. Aberrant glutamate signaling is thought to contribute to AD progression, as evidenced by the clinical use of memantine, a glutamate receptor antagonist, as an AD therapy, strongly implicating EAATs in the progression of AD. Finally, soluble A inhibits EAAT function during heightened neuronal activity. Interestingly, we recently showed that neuronal activity causes astrocyte depolarization, which drives voltage-dependent inhibition of EAAT function to enhance neuronal activation. In the parent R01, we use astrocyte-expressed genetically encoded voltage indicators (GEVIs) to optically quantify Vm and showed that neuronal activity depolarizes peripheral astrocyte processes (PAPs) with synapse-specificity. In this supplement request, we provide preliminary data that during normal aging astrocytes sporadically lose the expression of GLT1, GLAST, and Kir4.1 and take on a phenotype known as atypical astrocytes (AtAs). Importantly, AtAs are not a form of reactive astrocytosis. Preliminary data suggests AtAs are more abundant and occur earlier in the APPNL-G-F mouse model of AD and are seen in the aged human brain. Here we will test they hypothesis that because AtAs, which lack Kir4.1 and GLT-1, are abundant in the hippocampus of APPNL-G-F mice, astrocytes experience increased activity-induced depolarization, leading to exaggerated inhibition of glutamate uptake. This creates a situation in which increased neuronal activity could drive synergistic voltage-dependent and A-mediated EAAT inhibition in AD. We chose to use the APPNL-G-F model due to its early onset, overlapping with the normal development of AtAs, without APP overexpression. Using the APPNL-G-F mice, we will determine: (SA1) “Do hippocampal astrocytes in APPNL-G-F mice show increased Vm responses to neuronal activity?” and (SA2) “Is activity-dependent inhibition of glutamate uptake enhanced in the hippocampus of APPNL-G-F mice?“. Both increased activity-induced PAP depolarization and elevated A could alter activity-induced EAAT inhibition in APPNL-G-F mice. If so, this would position astrocyte-neuron interactions, K+ and glutamate homeostasis as key players in early AD progression and would motivate enhancing glutamate and K+ uptake to reduce AD-related pathology. When complete, we will know whether newly discovered changes in PAP Vm are exaggerated and contribute to aberrant glutamate excitation in APPNL-G-F mice. We will be poised to leverage these findings to enhance K+ and glutamate homeostasis to prevent pathological excitation in AD.