Reversal of Global Ischemia-Induced Cognitive Dysfunction by Delayed Inhibition of TRPM2 Ion Channels.

Hippocampal injury and cognitive impairments are common after cardiac arrest and stroke and do not have an effective intervention despite much effort. Therefore, we developed a new approach aimed at reversing synaptic dysfunction by targeting TRPM2 channels. Cardiac arrest/cardiopulmonary resuscitation (CA/CPR) in mice was used to investigate cognitive deficits and the role of the calcium-permeable ion channel transient receptor potential-M2 (TRPM2) in ischemia-induced synaptic dysfunction. Our data indicates that absence (TRPM2-/-) or acute inhibition of TRPM2 channels with tatM2NX reduced hippocampal cell death in males only, but prevented synaptic plasticity deficits in both sexes. Remarkably, administration of tatM2NX weeks after injury reversed hippocampal plasticity and memory deficits. Finally, TRPM2-dependent activation of calcineurin-GSK3ß pathway contributes to synaptic plasticity impairments. These data suggest persistent TRPM2 activity following ischemia contributes to impairments of the surviving hippocampal network and that inhibition of TRPM2 channels at chronic time points may represent a novel strategy to improve functional recovery following cerebral ischemia that is independent of neuroprotection.

Experimental pediatric stroke shows age-specific recovery of cognition and role of hippocampal Nogo-A receptor signaling.

Ischemic stroke is a leading cause of death worldwide and clinical data suggest that children may recover from stroke better than adults; however, supporting experimental data are lacking. We used our novel mouse model of experimental juvenile ischemic stroke (MCAO) to characterize age-specific cognitive dysfunction following ischemia. Juvenile and adult mice subjected to 45-min MCAO, and extracellular field recordings of CA1 neurons were performed to assess hippocampal synaptic plasticity changes after MCAO, and contextual fear conditioning was performed to evaluate memory and biochemistry used to analyze Nogo-A expression. Juvenile mice showed impaired synaptic plasticity seven days after MCAO, followed by full recovery by 30 days. Memory behavior was consistent with synaptic impairments and recovery after juvenile MCAO. Nogo-A expression increased in ipsilateral hippocampus seven days after MCAO compared to contralateral and sham hippocampus. Further, inhibition of Nogo-A receptors reversed MCAO-induced synaptic impairment in slices obtained seven days after juvenile MCAO. Adult MCAO-induced impairment of LTP was not associated with increased Nogo-A. This study demonstrates that stroke causes functional impairment in the hippocampus and recovery of behavioral and synaptic function is more robust in the young brain. Nogo-A receptor activity may account for the impairments seen following juvenile ischemic injury.

Endogenous Neuronal Replacement in the Juvenile Brain Following Cerebral Ischemia.

Replacement of dead neurons following ischemia, either via enhanced endogenous neurogenesis or stem cell therapy, has long been sought. Unfortunately, while various therapies that enhance neurogenesis or stem cell therapies have proven beneficial in animal models, they have all uniformly failed to truly replace dead neurons in the ischemic core to facilitate long-term recovery. Remarkably, we observe robust repopulation of medium-spiny neurons within the ischemic core of juvenile mice following experimental stroke. Despite extensive neuronal cell death in the injured striatum of both juveniles and adults at acute time points after ischemia (24 h and 7 d), mature newborn neurons replaced lost striatal neurons at 30 d post-ischemia. This neuronal repopulation was found only in juveniles, not adults, and importantly, was accompanied by enhanced post-ischemic behavioral recovery at 30 d. Ablation of neurogenesis using irradiation prevented neuronal replacement and functional recovery in MCAo-injured juvenile mice. In contrast, findings in adults were consistent with previous reports, that newborn neurons failed to mature and died, offering little therapeutic potential. These data provide support for neuronal replacement and consequent functional recovery following ischemic stroke and new targets in the development of novel therapies to treat stroke.

Juvenile cerebral ischemia reveals age-dependent BDNF-TrkB signaling changes: Novel mechanism of recovery and therapeutic intervention.

Global ischemia in childhood often leads to poor neurologic outcomes, including learning and memory deficits. Using our novel model of childhood cardiac arrest/cardiopulmonary resuscitation (CA/CPR), we investigate the mechanism of ischemia-induced cognitive deficits and recovery. Memory is impaired seven days after juvenile CA/CPR and completely recovers by 30 days. Consistent with this remarkable recovery not observed in adults, hippocampal long-term potentiation (LTP) is impaired 7-14 days after CA/CPR, recovering by 30 days. This recovery is not due to the replacement of dead neurons (neurogenesis), but rather correlates with brain-derived neurotrophic factor (BDNF) expression, implicating BDNF as the molecular mechanism underlying impairment and recovery. Importantly, delayed activation of TrkB receptor signaling reverses CA/CPR-induced LTP deficits and memory impairments. These data provide two new insights (1) endogenous recovery of memory and LTP through development may contribute to improved neurological outcome in children compared to adults and (2) BDNF-enhancing drugs speed recovery from pediatric cardiac arrest during the critical school ages.