Caffeine exacerbates seizure-induced death via postictal hypoxia.

Sudden unexpected death in epilepsy (SUDEP) is the leading epilepsy-related cause of premature mortality in people with intractable epilepsy, who are 27 times more likely to die than the general population. Impairment of the central control of breathing following a seizure has been identified as a putative cause of death, but the mechanisms underlying this seizure-induced breathing failure are largely unknown. Our laboratory has advanced a vascular theory of postictal behavioural dysfunction, including SUDEP. We have recently reported that seizure-induced death occurs after seizures invade brainstem breathing centres which then leads to local hypoxia causing breathing failure and death. Here we investigated the effects of caffeine and two adenosine receptors in two models of seizure-induced death. We recorded local oxygen levels in brainstem breathing centres as well as time to cessation of breathing and cardiac activity relative to seizure activity. The administration of the non-selective A1/A2A antagonist caffeine or the selective A1 agonist N6-cyclopentyladenosine reveals a detrimental effect on postictal hypoxia, providing support for caffeine modulating cerebral vasculature leading to brainstem hypoxia and cessation of breathing. Conversely, A2A activation with CGS-21680 was found to increase the lifespan of mice in both our models of seizure-induced death.

Febrile seizures lead to prolonged epileptiform activity and hyperoxia that when blocked prevents learning deficits.

OBJECTIVE: In adult brain tissue, oxygen levels typically remain in the normoxic zone, but status epilepticus results in hyperoxia, whereas brief self-terminating seizures lead to postictal hypoxia. The dynamic changes in oxygen levels and the underlying mechanisms are unknown in juveniles with febrile seizures. METHODS: Eight-day-old female and male rat pups were implanted with an electrode and oxygen-sensing optode in the hippocampus and then received once daily injections of lipopolysaccharide for 4 days to induce an immune response. Local partial pressure of oxygen (pO2 ) and local field potentials were recorded before, during, and after a heat-induced febrile seizure. Separate groups of pups received injections of vehicle or drugs targeting cyclooxygenase (COX)-1, COX-2, L-type calcium channels (LTCCs), and cannabinoid receptor type 1 (CB1) and transient receptor potential vanilloid-1 (TRPV1) receptors prior to febrile seizure induction to determine pO2 mechanisms. Following febrile seizures, a subset of pups were raised to young adulthood and then tested for learning impairments using the novel object recognition task. RESULTS: Febrile seizures resulted in predictable oxygen dynamics that were related to behavioral seizures and epileptiform activity. During a behavioral seizure, pO2 rapidly increased, rapidly decreased, and then returned to near baseline. When the behavioral seizure terminated, oxygen levels climbed into the hyperoxic zone during a time of prolonged epileptiform activity. When epileptiform activity terminated, oxygen levels slowly returned to baseline. A COX-1 antagonist prevented hyperoxia, whereas a COX-2 antagonist did not. An LTCC antagonist exacerbated hyperoxia. Boosting levels of an endocannabinoid also exacerbated hyperoxia, whereas blocking CB1 receptors and TRPV1 receptors reduced hyperoxia. Inhibiting TRPV1 receptors during a febrile seizure prevented learning deficits in young adult female rats. SIGNIFICANCE: Brain oxygenation during and following a febrile seizure has a distinct pattern and multiple mechanisms. Brain oxygen dynamics may be an important consideration in the development of treatments for febrile seizures.

The Stability of Glutamatergic Synapses Is Independent of Activity Level, but Predicted by Synapse Size.

Neuronal activity is thought to drive the remodeling of circuits in the mammalian cerebral cortex. However, its precise function in the underlying formation and elimination of glutamatergic synapses has remained controversial. To clarify the role of activity in synapse turnover, we have assessed the effects of inhibition of glutamate release from a sparse subset of cultured hippocampal neurons on synapse turnover. Sustained chemogenetic attenuation of release through presynaptic expression of a designer receptor exclusively activated by designer drugs (DREADD) had no effect on the formation or elimination of glutamatergic synapses. Sparse expression of tetanus neurotoxin light chain (TeNT-LC), a synaptobrevin-cleaving protease that completely abolishes neurotransmitter release, likewise did not lead to changes in the rate of synapse elimination, although it reduced the rate of synapse formation. The stability of active and silenced synapses correlated with measures of synapse size. While not excluding a modulatory role in synapse elimination, our findings show that synaptic activity is neither required for the removal nor the maintenance of glutamatergic synapses between hippocampal neurons. Our results also demonstrate that the stability of glutamatergic synapses scales with their size irrespective of their activity.