Increased astrocytic GLT-1 expression in tripartite synapses is associated with SCI-induced hyperreflexia

• Published in: Journal of neurophysiology Vol. 130; no. 5; pp. 1358 - 1366
• Main Authors: Benson, Curtis A, King, Jared F, Kauer, Sierra D, Waxman, Stephen G, Tan, Andrew M
• Format: Journal Article
• Language: English
• Published: United States 01.11.2023
• Subjects: Animals; Astrocytes - metabolism; Motor Neurons - physiology; Reflex, Abnormal; Spinal Cord - metabolism; Spinal Cord Injuries - complications; Spinal Cord Injuries - metabolism; Synapses - metabolism; spinal cord injury; spasticity; astrocytes; synapse
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/JN.00234.2023

Spasticity is a chronic neurological complication associated with spinal cord injury (SCI), characterized by increased muscle tone and stiffness. A physiological sign of spasticity is hyperreflexia, evident by the loss of evoked rate-dependent depression (RDD) in the H-reflex. Although previous work has shown that SCI-induced astrogliosis contributes to hyperexcitability disorders, including neuropathic pain and spasticity, it is unclear how reactive astrocytes can modulate synaptic transmission within the injured spinal cord. To study astrocytes' role in post-SCI hyperreflexia, we examined glutamate transporter-1 (GLT-1) and postsynaptic density protein 95 (PSD-95) proteins in astrocytes and neurons, respectively, within the ventral horn (lamina IX) below the level of injury (spinal segment L4-5). The close juxtaposition of GLT-1 and PSD-95 markers is a molecular correlate of tripartite synapses and is thought to be a key element in the astrocyte-induced plasticity of neuronal synapses. Our study compared animals with and without SCI-induced hyperreflexia and spasticity and investigated potential synaptic abnormalities associated with astrocyte involvement. As expected, 4 wk after SCI, we observed a loss in evoked H-reflex RDD in hindlimb electromyogram recordings, i.e., hyperreflexia, in contrast to uninjured sham. Importantly, our main findings show a significant increase in the presence of GLT-1-PSD-95 tripartite synapses in the ventral spinal cord motor regions of animals exhibiting SCI-induced hyperreflexia. Taken together, our study suggests the involvement of astrocyte-neuron synaptic complexes in the plasticity-driven progression of chronic spasticity. The role of astrocytes in H-reflex hyperexcitability following SCI remains understudied. Our findings establish a relationship between GLT-1 expression, its proximity to neuronal PSD-95 in the spinal cord ventral horn, and the loss of H-reflex RDD, i.e., hyperreflexia. Our findings provide a new perspective on synaptic alterations and the development of SCI-related spasticity.