Astrocyte glutamate uptake coordinates experience‐dependent, eye‐specific refinement in developing visual cortex

Abstract

The uptake of glutamate by astrocytes actively shapes synaptic transmission, however its role in the development and plasticity of neuronal circuits remains poorly understood. The astrocytic glutamate transporter, GLT1 is the predominant source of glutamate clearance in the adult mouse cortex. Here, we examined the structural and functional development of the visual cortex in GLT1 heterozygous (HET) mice using two‐photon microscopy, immunohistochemistry and slice electrophysiology. We find that though eye‐specific thalamic axonal segregation is intact, binocular refinement in the primary visual cortex is disrupted. Eye‐specific responses to visual stimuli in GLT1 HET mice show altered binocular matching, with abnormally high responses to ipsilateral compared to contralateral eye stimulation and a greater mismatch between preferred orientation selectivity of ipsilateral and contralateral eye responses. Furthermore, we observe an increase in dendritic spine density in the basal dendrites of layer 2/3 excitatory neurons suggesting aberrant spine pruning. Monocular deprivation induces atypical ocular dominance plasticity in GLT1 HET mice, with an unusual depression of ipsilateral open eye responses; however, this change in ipsilateral responses correlates well with an upregulation of GLT1 protein following monocular deprivation. These results demonstrate that a key function of astrocytic GLT1 function during development is the experience‐dependent refinement of ipsilateral eye inputs relative to contralateral eye inputs in visual cortex.

Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?

“…Concerning synaptic activity, astrocytes contact both the pre-synaptic axon terminal and post-synaptic dendritic spines, creating the so-called “tripartite synapse”. As a result of these connections, astrocytes can sense neuronal activity and in turn modulate synaptic transmission and plasticity, for instance by the re-uptake of glutamate from the synaptic cleft through glutamate transporters [ 22 , 23 , 24 ] or by releasing gliotransmitters (e.g., glutamate, ATP, and D-serine) [ 25 , 26 , 27 ].…”

Heterosynaptic Plasticity and the Experience-Dependent Refinement of Developing Neuronal Circuits

“…GLT1 is an astrocytic glutamate transporter responsible for 80–90% of synaptic glutamate clearance in the adult mouse cortex, and neuronal activity regulates the expression and subcellular trafficking of GLT1 to active synapses (Benediktsson et al, 2012 ). GLT1 expression in V1 begins at eye opening and peaks at the start of the critical period (Sipe et al, 2021 ). GLT1 heterozygous mice have a 40% reduction in GLT1 expression, and in V1 this reduction leads to mismatched contralateral and ipsilateral orientation selective responses in layer 2/3 neurons, with the ipsilateral responses abnormally high and poorly tuned relative to controls.…”

Glia Regulate the Development, Function, and Plasticity of the Visual System From Retina to Cortex

“…As discussed above, glutamate transporters have been shown to mediate responsiveness of astrocytes to visual stimulation in the primary visual cortex of ferrets (Schummers et al, 2008); as such, understanding how astrocytic glutamate transporters influence the development of the visual system is of particular interest. GLT-1 (EAAT2) is the dominant glutamate transporter expressed by astrocytes in the visual cortex of mice, and visual experience has been shown to increase GLT-1 expression levels in V1 astrocytes throughout development (Sipe et al, 2021). In GLT-1 heterozygous (HET) mice, astrocytic levels of GLT-1 are reduced by approximately 50% in the visual cortex.…”