Abstract 15651: Astrocytic Chordin-Like 1 Regulates AMPAR Synaptic Content and Motor Recovery in a Mouse Model of Ischemic Stroke

Abstract

Introduction: Ischemic stroke triggers a series of molecular events that impairs receptor levels at excitatory synapses. AMPA receptors (AMPARs), the main excitatory receptors in the mammalian brain, are crucial in maintaining proper brain function. In response to ischemic stroke, their subunit composition and location at the synapse are deeply altered and trigger apoptotic cell death cascades. We previously found that Chordin-like 1 (Chrdl1), an astrocyte-derived protein that regulates AMPARs, is highly upregulated in the peri-infarct region at early stages after stroke (1 and 7 days post-stroke, dps). When Chrdl1 was absent, neurons were protected from stroke-induced structural degeneration. Hypothesis: Elimination of Chrdl1 prevents stroke-induced aberrant AMPAR synaptic levels, limits AMPAR-mediated apoptotic cascades and alleviates behavioral deficits. Methods: We used photothrombosis to model ischemic stroke in the motor cortex of adult male and female WT and Chrdl1 KO mice and performed analyses at 1 and 7 dps in the peri-infarct area. We used fluorescent in situ hybridization to analyze mRNA levels of Chrdl1, immunohistochemistry to determine synaptic AMPAR levels and subunit composition, TUNEL to determine apoptotic cell death, MRI to monitor the progression of injury volume, and adhesive removal and grid walk tests to assess sensorimotor and motor behaviors. Results: WT mice, after photothrombotic injury showed important impairments in the AMPAR synaptic distribution and composition. This aberrant AMPAR subunit composition and location at synapses was abolished in Chrdl1 KO mice. This resulted in reduced apoptotic cell death and faster motor recovery in Chrdl1 KO mice compared to WT in both male and female mice. Conclusions: This study shows that targeting Chrdl1 has therapeutic potential to reduce apoptotic cell death and aid motor recovery after ischemic stroke via synaptic regulation of AMPARs. Astrocyte-derived proteins, such as Chrdl1, may represent new molecular targets that can restore synapses to favor functional recovery after ischemic stroke.