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1. Estimating the glutamate transporter surface density in distinct sub-cellular compartments of mouse hippocampal astrocytes

   https://doi.org/10.1371/journal.pcbi.1009845  

   Rǎdulescu, Anca R. ; Todd, Gabrielle C. ; Williams, Cassandra L. ; Bennink, Benjamin A. ; Lemus, Alex A. ; Chesbro, Haley E. ; Bourgeois, Justin R. ; Kopec, Ashley M. ; Zuloaga, Damian G. ; Scimemi, Annalisa ( February 2022 , PLOS Computational Biology)

   Berry, Hugues (Ed.)

   Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity in the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft. 

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2. Estimating the glutamate transporter surface density in distinct sub-cellular compartments of mouse hippocampal astrocytes

   Rǎdulescu, AR ; Todd, GC ; Williams, CL ; Bennink, BA ; Lemus, AA ; Chesbro, HE ; Bourgeois, JR ; Kopec, AM ; Zuloaga, DG ; Scimemi, A. ( February 2022 , PLoS computational biology)

   Berry, H. (Ed.)

   Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity in the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft. 

   more » « less
3. Estimating the glutamate transporter surface density in distinct sub-cellular compartments of mouse hippocampal astrocytes.

   Rǎdulescu, AR ; Todd, GC ; Williams, CL ; Bennink, BA ; Lemus, AA ; Chesbro, HE ; Bourgeois, JR ; Kopec, AM ; Zuloaga, DG ; Scimemi, A. ( February 2022 , PLoS computational biology)

   Berry, H. (Ed.)

   Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity in the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft. 

   more » « less
4. Estimating the glutamate transporter surface density in distinct sub-cellular compartments of mouse hippocampal astrocytes

   Anca R Rǎdulescu, Gabrielle C ( February 2022 , PLoS computational biology)

   Hugues Berry (Ed.)

   Glutamate transporters preserve the spatial specificity of synaptic transmission by limiting glutamate diffusion away from the synaptic cleft, and prevent excitotoxicity by keeping the extracellular concentration of glutamate at low nanomolar levels. Glutamate transporters are abundantly expressed in astrocytes, and previous estimates have been obtained about their surface expression in astrocytes of the rat hippocampus and cerebellum. Analogous estimates for the mouse hippocampus are currently not available. In this work, we derive the surface density of astrocytic glutamate transporters in mice of different ages via quantitative dot blot. We find that the surface density of glial glutamate transporters is similar in 7-8 week old mice and rats. In mice, the levels of glutamate transporters increase until about 6 months of age and then begin to decline slowly. Our data, obtained from a combination of experimental and modeling approaches, point to the existence of stark differences in the density of expression of glutamate transporters across different sub-cellular compartments, indicating that the extent to which astrocytes limit extrasynaptic glutamate diffusion depends not only on their level of synaptic coverage, but also on the identity of the astrocyte compartment in contact with the synapse. Together, these findings provide information on how heterogeneity in the spatial distribution of glutamate transporters in the plasma membrane of hippocampal astrocytes my alter glutamate receptor activation out of the synaptic cleft. 

   more » « less
5. Suppression of food restriction‐evoked hyperactivity in activity‐based anorexia animal model through glutamate transporters GLT‐1 at excitatory synapses in the hippocampus

   https://doi.org/10.1002/syn.22197  

   Bilash, Olesia M. ; Actor‐Engel, Hannah S. ; Sherpa, Ang D. ; Chen, Yi‐Wen ; Aoki, Chiye ( March 2021 , Synapse)

   Severe voluntary food restriction is the defining symptom of anorexia nervosa (AN), but anxiety and excessive exercise are maladaptive symptoms that contribute significantly to the severity of AN and which individuals with AN have difficulty suppressing. We hypothesized that the excitability of hippocampal pyramidal neurons, known to contribute to anxiety, leads to the maladaptive behavior of excessive exercise. Conversely, since glutamate transporter GLT‐1 dampens the excitability of hippocampal pyramidal neurons through the uptake of ambient glutamate and suppression of the GluN2B‐subunit containing NMDA receptors (GluN2B‐NMDARs), GLT‐1 may contribute toward dampening excessive exercise. This hypothesis was tested using the mouse model of AN, called activity‐based anorexia (ABA), whereby food restriction evokes the maladaptive behavior of excessive wheel running (food restriction‐evoked running, FRER). We tested whether individual differences in ABA vulnerability of mice, quantified based on FRER, correlated with individual differences in the levels of GLT‐1 at excitatory synapses of the hippocampus. Electron microscopic immunocytochemistry (EM‐ICC) was used to quantify GLT‐1 levels at the excitatory synapses of the hippocampus. The FRER seen in individual mice varied more than 10‐fold, and Pearson correlation analyses revealed a strong negative correlation (p = .02) between FRER and GLT‐1 levels at the axon terminals of excitatory synapses and at the surrounding astrocytic plasma membranes. Moreover, synaptic levels of GluN2B‐NMDARs correlated strongly with GLT‐1 levels at perisynaptic astrocytic plasma membranes. There is at present no accepted pharmacotherapy for AN, and little is known about the etiology of this deadly illness. Current findings suggest that drugs increasing GLT‐1 expression may reduce AN severity through the reduction of GluN2B‐NMDAR activity.

    

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