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The motor neuron cell autonomous and non\u2010cell autonomous disease mechanisms driving early glutamatergic dysfunction, a therapeutically targetable phenotype prior to motor neuron cell loss, remain unclear. Using microelectrode array analysis, we demonstrate that the secretome and cell surface proteins needed for proper synaptic modulation are likely disrupted in human SMA astrocytes and lead to diminished motor neuron activity. While healthy astrocyte conditioned media did not improve SMA motor neuron activity, SMA motor neurons robustly responded to healthy astrocyte neuromodulation in direct contact cultures. This suggests an important role of astrocyte synaptic\u2010associated plasma membrane proteins and contact\u2010mediated cellular interactions for proper motor neuron function in SMA. Specifically, we identified a significant reduction of the glutamate Na<jats:sup>+<\/jats:sup> dependent excitatory amino acid transporter EAAT1 within human SMA astrocytes and SMA lumbar spinal cord tissue. The selective inhibition of EAAT1 in healthy co\u2010cultures phenocopied the diminished neural activity observed in SMA astrocyte co\u2010cultures. Caveolin\u20101, an SMN\u2010interacting protein previously associated with local translation at the plasma membrane, was abnormally elevated in human SMA astrocytes. Although lentiviral SMN delivery to SMA astrocytes partially rescued EAAT1 expression, limited activity of healthy motor neurons was still observed in SMN\u2010transduced SMA astrocyte co\u2010cultures. Together, these data highlight the detrimental impact of astrocyte\u2010mediated disease mechanisms on motor neuron function in SMA and that SMN delivery may be insufficient to fully restore astrocyte function at the synapse.<\/jats:p>","DOI":"10.1002\/glia.24340","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T07:21:34Z","timestamp":1674112894000},"page":"1311-1332","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Diminished motor neuron activity driven by abnormal astrocytic <scp>EAAT1<\/scp> glutamate transporter activity in spinal muscular atrophy is not fully restored after lentiviral <scp>SMN<\/scp> delivery"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2408-0407","authenticated-orcid":false,"given":"Emily","family":"Welby","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Neurobiology and Anatomy Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9676-8548","authenticated-orcid":false,"given":"Allison D.","family":"Ebert","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Neurobiology and Anatomy Medical College of Wisconsin  Milwaukee Wisconsin 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