Targeting Astrocytes to Enhance Synaptic Plasticity and Repair

This project investigates the molecular mechanisms that control neuronal synaptic plasticity and remodeling during the critical period, a period of time in the developing brain when it is possible to remodel synapses through experience. We approach this by focusing on the contribution of a class of glial cell to this process, the astrocyte. Astrocytes are an abundant cell type in the cortex, where they interact with neurons and synapses. In the developing brain, astrocytes strongly regulate neuronal synapse formation and function, mainly via the release of secreted factors. Recent studies have suggested that adult astrocytes inhibit synaptic plasticity, however the molecular mechanisms they use to do this are not understood. To address this question we performed an in vivo screen to ask how astrocytes in the visual cortex change their properties after induction of synaptic plasticity, and between the critical period and adulthood. Using RNA sequencing specifically of astrocyte mRNA, we identified candidate factors that are altered in astrocytes in response to multiple plasticity manipulations. Preliminary testing of one candidate, that is normally low during the critical period and high in the adult brain, showed that over- expressing this candidate in astrocytes during the critical period inhibited synaptic plasticity. Aim 1 of this project asks how this factor is inhibiting plasticity, by studying synaptic function, synaptic glutamate receptor composition and dendritic spine stability. Aim 2 asks if knocking down this candidate in adult astrocytes is sufficient to re-open plasticity in the adult brain. These experiments will identify if manipulating astrocytes in the adult brain is sufficient to reinduce synaptic plasticity, and in future we will ask if these same manipulations can be used to stimulate synaptic repair in disorders where synapses are lost.

Grant Recipients

Dr. Nicola Allen

Nicola Allen is an Associate Professor at the Salk Institute for Biological Studies, USA. She received her PhD working with David Attwell at University College London studying neuronal responses to ischemia, and performed Postdoctoral research with Ben Barres at Stanford University where she identified how astrocytes regulate the formation of functional synapses between neurons. Current work in her lab investigates how neuronal synapses are regulated throughout life: from the formation of synapses during development, to the remodeling of synapses in the adult in response to experience, to the loss of synapses in aging. This is approached not just by studying neurons, but by asking how non-neuronal glial cells, specifically astrocytes, regulate synapse number and synaptic function. The goal is to use this knowledge of astrocytes to repair synapses when they are dysfunctional in diverse neurological disorders.