Delayed administration of type II ampakines enhance synaptic plasticity and cognitive recovery in juvenile global cerebral ischemia

Children who experience cardiac arrest often suffer lasting neurological deficits, including impairments to learning and memory, due to global cerebral ischemia (GCI). Using a juvenile mouse model of cardiac arrest and resuscitation, we investigated the long-term effects of GCI and potential therapeutic interventions. Following juvenile GCI, long-term potentiation (LTP) and memory were impaired for several weeks followed by endogenous recovery coinciding with changes in brain-derived neurotrophic factor (BDNF) levels, an essential regulator of synaptic plasticity specifically in juveniles but not adults. Given that BDNF is unstable in plasma and cannot cross the blood-brain barrier, we explored the use of type II ampakines, positive allosteric modulators of AMPA receptors, to increase BDNF protein levels in the brain. In vivo administration of type II ampakines 14 days after GCI increased hippocampal BDNF levels, restored LTP, and improved hippocampal-dependent memory and learning behavior. These findings highlight the potential of type II ampakines as an innovative therapeutic intervention to restore synaptic and cognitive function at delayed time points after juvenile GCI.