👤 Paco S Herson

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. Show less

Post-stroke cognitive impairment and dementia (PSCID) affects many survivors of large vessel cerebral ischemia. The molecular pathways underlying PSCID are poorly defined but may overlap with neurodegenerative pathophysiology. Specifically, synaptic dysfunction after stroke may be directly mediated by alterations in the levels of amyloid beta (Aβ), the peptide that accumulates in the brains of Alzheimer's disease (AD) patients. In this study, we use the transient middle cerebral artery occlusion (MCAo) model in young adult mice to evaluate if a large vessel stroke increases brain soluble Aβ levels. We show that soluble Aβ40 and Aβ42 levels are increased in the ipsilateral hippocampus in MCAo mice 7 days after the injury. We also analyze the level and activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), an enzyme that generates Aβ in the brain, and observe that BACE1 activity is increased in the ipsilateral hippocampus of the MCAo mice. Finally, we highlight that treatment of MCAo mice with a BACE1 inhibitor during the recovery period rescues stroke-induced deficits in hippocampal synaptic plasticity. These findings support a molecular pathway linking ischemia to alterations in BACE1-mediated production of Aβ, and encourage future studies that evaluate whether targeting BACE1 activity improves the cognitive deficits seen with PSCID. Show less