323 - Novel recovery mechanism of synaptic dysfunction and learning behavior following global ischemia in the developing brain via AMPAkine-induced BDNF expression.
Assistant Professor University of Colorado School of Medicine University of Colorado Denver School of Medicine Aurora, Colorado, United States
Background: Global cerebral ischemia (GCI) in the developing brain often leads to learning and memory deficits through school age. We have demonstrated that enhanced BDNF-TrkB signaling contributes to recovery of hippocampal function after juvenile GCI (GCI). AMPAkines are allosteric modulators of AMPA-receptors and some have been shown to augment BDNF expression. Objective: We hypothesize AMPAkines which augment BDNF will reverse synaptic dysfunction following GCI. Design/Methods: Juvenile mice (PND 20-25) were subjected to 8-minute cardiac arrest and resuscitated. Long-term potentiation (LTP), a cellular model for learning and memory, was measured in acute hippocampal CA1 slices following theta-burst stimulation (40 pulses 100Hz). Increase in field excitatory post-synaptic potential slope 60 minutes after TBS was analyzed as a measurement of LTP (baseline 100%). Contextual fear conditioning (CFC)was performed to evaluate hippocampal-dependent learning and memory. Mice are exposed to a novel environment and after habituation in the environment given a mild foot shock (1 mA for 1 second) and then returned to their home cage. 24 hr after the foot shock, mice are placed again in the CFC environment and freezing behavior is analyzed during a 5 min test. Memory of the environment evokes a freezing behavior. BDNF expression was measured using ELISA from hippocampal tissue. Data presented as mean±SD. Results: BDNF expression is decreased at 14 days after GCI compared to sham (n=4, p< 0.05). Injection of AMPAkine LY404187 (1mg/kg) 14 days after GCI increased BDNF expression (n=4, p< 0.05) whereas injection of a different AMPAkine, IDRA-21 (1-5mg/kg) had no effect on post-GCI decreased BDNF expression (n=4). Vehicle-treated slices revealed impaired LTP 14 days after jGCI but ex vivo exposure to LY404187 (25μM) results in recovery of LTP in paired experiments (sham:155±13%; GCI/vehicle:112±12%; GCI/LY404187:156±13%, n=4, p=0.01). Similar paired experimental design found no recovery with exposure to IDRA-21 (vehicle:103±10% vs IDRA-21:106±11%, n=5 each). Intravenous administration of LY404187 (1mg/kg) on day 13 post-GCI rescued CFC impairment on 24 hours later. Sham mice given vehicle froze 61±12% (n=6) of the time compared to GCI mice freezing 20±3% (n=5) after receiving vehicle. Administration of LY404187 had no effect in sham mice (64±15%, n=5), but did recovery learning and memory following GCI (53±13%, n=5, p< 0.05).
Conclusion(s): These data indicate that delivery of AMPAkine LY404187 14 days after GCI enhances BDNF expression and recovers hippocampal synaptic dysfunction following global ischemia in the juvenile brain.
