Abstract 14: Synaptic Remodeling after Stroke Enhanced by Transplanted Human Neural Stem Cells is Coincident with Functional Recovery
Background: Stem cell transplantation (Tx) has emerged as a promising new experimental treatment for stroke; understanding its mechanism of action will facilitate the translation of stem cell therapy to the clinic. The ultimate change in brain plasticity is manifested at the synaptic level, however, the synaptic remodeling after stem cell therapy remains unknown. Here we evaluate the effect of transplanted human neural progenitor cells (hNPCs) on the peri-infarct synaptic remodeling in the post-ischemic brain.
Materials and Methods: We use array tomography, a high-resolution proteomic imaging method, to determine how hNPCs affect the number and subtype of glutamate and GABA synapses after stroke. Vehicle or hNPCs were transplanted into the ischemic cortex of Nude rats 7 days after distal middle cerebral artery occlusion. Neurological recovery was assessed weekly using a battery of behavioral tests. The arrays of serial ultrathin sections (70 nm), removed from the peri-infarct cortex at 1 and 4 weeks post-Tx, were stained using multiple synaptic markers and imaged in cortical layer 2/3 and 5. Computational analysis of the resultant staining pattern was used to identify and quantify subtypes of glutamate and GABA synapses.
Results: Tx of hNPCs significantly improved behavioral recovery after stroke compared to vehicle-treated rats (4 weeks post-transplantation; p<0.01) without altering the infarct size. hNPC-treated rats had a higher density of VGluT1-containing glutamate synapses (0.223 vs 0.185 synapses/μm3, p<0.05), and GluA2-containing glutamate synapses (0.091 vs 0.069 synapses/μm3, p<0.05) in layer 5 at 4 weeks post-Tx, compared to vehicle-treated rats. However, hNPCs had did not alter total number of glutamate synapses. This synaptic increase was cortical layer-specific observed in layer 5 but not .in layer 2/3. hNPCs had no detectable effect on the density of GABA synapses in either layer 5 or 2/3 at 1 week or 4 weeks post-Tx.
Conclusions: These results provide novel new information about the organization of synaptic circuitry and its plasticity after stem cell therapy. These data suggest that stem cells alter the subunit composition of glutamate synapses after stroke and this is coincident with stem cell-induced functional recovery.
Author Disclosures: T. Hiu: None. T. Bliss: None. N. Manley: None. E. Wang: None. Y. Nishiyama: None. G. Sun: None. A. Olson: None. K. Micheva: None. G. Wang: None. J. Berry: None. S. Smith: None. G. Steinberg: None.
- © 2014 by American Heart Association, Inc.