The Role of Kainate Receptors in the Pathophysiology of Hypoxia-Induced Seizures in the Neonatal Mouse.

Kainate receptors (KARs) are glutamate receptors with peak expression during late embryonic and early postnatal periods. Altered KAR-mediated neurotransmission and subunit expression are observed in several brain disorders, including epilepsy. Here, we examined the role of KARs in regulating seizures in neonatal C57BL/6 mice exposed to a hypoxic insult. We found that knockout of the GluK2 subunit, or blockade of KARs by UBP310 reduced seizure susceptibility during the period of reoxygenation. Following the hypoxic insult, we observed an increase in excitatory neurotransmission in hippocampal CA3 pyramidal cells, which was blocked by treatment with UBP310 prior to hypoxia. Similarly, we observed increased excitatory neurotransmission in CA3 pyramidal cells in an in vitro hippocampal slice model of hypoxic-ischemia. This increase was absent in slices from GluK2-/- mice and in slices treated with UBP310, suggesting that KARs regulate, at least in part, excitatory synaptic neurotransmission following in vivo hypoxia in neonatal mice. Data from these hypoxia models demonstrate that KARs, specifically those containing the GluK2 subunit, contribute to alterations in excitatory neurotransmission and seizure susceptibility, particularly during the reoxygenation period, in neonatal mice. Therapies targeting KARs may prove successful in treatment of neonates affected by hypoxic seizures.

Suicidality in a 27-year-old Male with Obsessive Compulsive Disorder.

This is a case report of a 27-year-old male with obsessive compulsive disorder (OCD) and anxiety who presented to a community hospital with suicidality. OCD is a rare psychiatric disorder characterized by recurrent and intrusive thoughts or obsessions and/or repetitive behaviors aimed at alleviating these thoughts known as compulsions. Management of this condition includes comprehensive evaluation of comorbidities and suicidality along with pharmacotherapy and a specific form of cognitive behavioral therapy (CBT) called exposure and response prevention (EX/RP or ERP). This unique case report highlights the necessity of a thorough and individualized approach to treatment for each patient in order to maximize the outcomes of care.

Phosphatase inhibition prevents the activity-dependent trafficking of GABAA receptors during status epilepticus in the young animal.

OBJECTIVES: To determine if the activity-dependent trafficking of γ2 subunit-containing γ-aminobutyric acid type A receptors (GABAA Rs) that has been observed in older animals and posited to contribute to benzodiazepine pharmacoresistance during status epilepticus (SE) is age-dependent, and to evaluate whether blockade of protein phosphatases can inhibit or reverse the activity-dependent plasticity of these receptors. METHODS: The efficacy and potency of diazepam 0.2-10 mg/kg administered 3 or 60 min after the onset of a lithium/pilocarpine-induced seizure in postnatal day 15-16 rats was evaluated using video-electroencephalography (EEG) recordings. The surface expression of γ2 subunit-containing GABAA Rs was assessed using a biotinylation assay, and GABAA R-mediated miniature inhibitory postsynaptic currents (mIPSCs) were recorded using whole-cell patch-clamp recording techniques from dentate granule cells in hippocampal slices acutely obtained 60 min after seizure onset (SE-treated). The effect of the protein phosphatase inhibitors FK506 and okadaic acid (OA) on the surface expression of these receptors was determined in organotypic slice cultures exposed to high potassium and N-methyl-d-aspartate (NMDA) or in SE-treated slices. RESULTS: Diazepam terminated seizures of 3 min but not 60 min duration, even at the highest dose. In the SE-treated slices, the surface expression of γ2 subunit-containing GABAA Rs was reduced and the amplitude of the mIPSCs was diminished. Inhibition of protein phosphatases prevented the activity-induced reduction of the γ2 subunit-containing GABAA Rs in organotypic slice cultures. Furthermore, treatment of SE-treated slices with FK506 or OA restored the surface expression of the γ2 subunit-containing GABAA Rs and the mIPSC amplitude. SIGNIFICANCE: This study demonstrates that the plasticity of γ2 subunit-containing GABAA Rs associated with the development of benzodiazepine resistance in young and adult animals is similar. The findings of this study suggest that the mechanisms regulating the activity-dependent trafficking of GABAA Rs during SE can be targeted to develop novel adjunctive therapy for the treatment of benzodiazepine-refractory SE.