Progesterone Receptor Activation Regulates Sensory Sensitivity and Migraine Susceptibility.

Women develop chronic pain during their reproductive years more often than men, and estrogen and progesterone regulate this susceptibility. We tested whether brain progesterone receptor (PR) signaling regulates pain susceptibility. During the estrous cycle, animals were more sensitive to mechanical stimulus during the estrus stage than in the diestrus stage, suggesting a role for reproductive hormones, estrogen, and progesterone.

Progesterone receptor activation regulates sensory sensitivity.

Women develop chronic pain during their reproductive years more often than men, and estrogen and progesterone regulate this susceptibility. We tested whether brain progesterone receptor (PR) signaling regulates pain susceptibility. During the estrous cycle, animals were more sensitive to pain during the estrus stage than in the diestrus stage, suggesting a role for reproductive hormones, estrogen, and progesterone.

Limbic progesterone receptors regulate spatial memory.

Progesterone and its receptors (PRs) participate in mating and reproduction, but their role in spatial declarative memory is not understood. Male mice expressed PRs, predominately in excitatory neurons, in brain regions that support spatial memory, such as the hippocampus and entorhinal cortex (EC). Furthermore, segesterone, a specific PR agonist, activates neurons in both the EC and hippocampus.

Increased glutamatergic synaptic transmission during development in layer II/III mouse motor cortex pyramidal neurons.

Postnatal maturation of the motor cortex is vital to developing a variety of functions, including the capacity for motor learning. The first postnatal weeks involve many neuronal and synaptic changes, which differ by region and layer, likely due to different functions and needs during development. Motor cortex layer II/III is critical to receiving and integrating inputs from somatosensory cortex and generating attentional signals that are important in motor learning and planning.

Limbic progesterone receptor activity enhances neuronal excitability and seizures.

Objective: Emerging evidence raises the possibility that progesterone receptor (PR) signaling may contribute to the reproductive hormone fluctuation-linked seizure precipitation, called catamenial epilepsy. Therefore, we studied PR isoform expression in limbic regions involved in temporal lobe epilepsy and the effect of PR activation on neuronal activity and seizures.

Methods: We evaluated PR expression in the limbic regions, entorhinal cortex (EC), hippocampus, and amygdala in female rats using quantitative real-time polymerase chain reaction (qRT-PCR).

Difluoroboron β-diketonate polylactic acid oxygen nanosensors for intracellular neuronal imaging.

Critical for metabolism, oxygen plays an essential role in maintaining the structure and function of neurons. Oxygen sensing is important in common neurological disorders such as strokes, seizures, or neonatal hypoxic-ischemic injuries, which result from an imbalance between metabolic demand and oxygen supply. Phosphorescence quenching by oxygen provides a non-invasive optical method to measure oxygen levels within cells and tissues.

Progesterone modulates neuronal excitability bidirectionally.

Progesterone acts on neurons directly by activating its receptor and through metabolic conversion to neurosteroids. There is emerging evidence that progesterone exerts excitatory effects by activating its cognate receptors (progesterone receptors, PRs) through enhanced expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Progesterone metabolite 5α,3α-tetrahydro-progesterone (allopregnanolone, THP) mediates its anxiolytic and sedative actions through the potentiation of synaptic and extrasynaptic γ-aminobutyric acid type-A receptors (GABARs).

Neocortical injury-induced status epilepticus.

Objective: To characterize neocortical onset status epilepticus (SE) in the C57BL/6J mouse.

Methods: We induced SE by administering homocysteine 16-18 hours after cobalt (Co) implantation. SE was monitored by video and electroencephalography (EEG).

Characterization of kindled VGAT-Cre mice as a new animal model of temporal lobe epilepsy.

Objective: Development of novel therapies for temporal lobe epilepsy is hindered by a lack of models suitable for drug screening. While testing the hypothesis that "inhibiting inhibitory neurons" was sufficient to induce seizures, it was discovered that a mild electrical kindling protocol of VGAT-Cre mice led to spontaneous motor and electrographic seizures. This study characterizes these seizures and investigates the mechanism.

The Need to Intervene Before Time Point 2: Evidence From Clinical and Animal Data That Status Epilepticus Damages the Brain.

Status epilepticus, a condition characterized by abnormally prolonged seizures, has the potential to cause irreversible, structural or functional, injury to the brain. Unfavorable consequences of these seizures include mortality, the risk of developing epilepsy, and cognitive impairment. We highlight key findings of clinical and laboratory studies that have provided insights into aspects of cell death, and anatomical and functional alterations triggered by status epilepticus that support the need to intervene before time point 2, the time after which the risk of these long-term consequences increases.

The Frail Male: Early Life Inflammation Promotes Chloride Loading in Adult Male Mice.

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Reduced neurosteroid potentiation of GABA receptors in epilepsy and depolarized hippocampal neurons.

Objective: Neurosteroids regulate neuronal excitability by potentiating γ-aminobutyric acid type-A receptors (GABARs). In animal models of temporal lobe epilepsy, the neurosteroid sensitivity of GABARs is diminished and GABAR subunit composition is altered. We tested whether similar changes occur in patients with epilepsy and if depolarization-induced increases in neuronal activity can replicate this effect.

A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat.

Children with malformations of cortical development (MCD) are at risk for epilepsy, developmental delays, behavioral disorders, and intellectual disabilities. For a subset of these children, antiseizure medications or epilepsy surgery may result in seizure freedom. However, there are limited options for treating or curing the other conditions, and epilepsy surgery is not an option in all cases of pharmacoresistant epilepsy.

α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor Plasticity Sustains Severe, Fatal Status Epilepticus.

Objective: Generalized convulsive status epilepticus is associated with high mortality. We tested whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor plasticity plays a role in sustaining seizures, seizure generalization, and mortality observed during focal onset status epilepticus. We also determined whether modified AMPA receptors generated during status epilepticus could be targeted with a drug.

Progesterone receptor activation regulates seizure susceptibility.

Objective: Progesterone is a potent neuromodulator that exerts effects on the brain through neurosteroids, progesterone receptors (PRs), and other molecules. Whether PR activation regulates seizures is not known. We determined whether PR activation increased seizure susceptibility.

Parallel pathways of seizure generalization.

Generalized convulsive status epilepticus is a life-threatening emergency, because recurrent convulsions can cause death or injury. A common form of generalized convulsive status epilepticus is of focal onset. The neuronal circuits activated during seizure spread from the hippocampus, a frequent site of seizure origin, to the bilateral motor cortex, which mediates convulsive seizures, have not been delineated.

Mechanisms of status epilepticus: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor hypothesis.

Prolonged seizures of status epilepticus (SE) result from failure of mechanisms of seizure termination or activation of mechanisms that sustain seizures. Reduced γ-aminobutyric acid type A receptor-mediated synaptic transmission contributes to impairment of seizure termination. However, mechanisms that sustain prolonged seizures are not known.

Status epilepticus: Role for etiology in determining response to benzodiazepines.

Objective: Clinical factors contributing to benzodiazepine failure in treating status epilepticus (SE) include suboptimal dosing and seizure duration. As many benzodiazepine-refractory episodes of SE arise from acute etiologies, we sought to determine whether etiology impacts SE treatment.

Methods: The potency of diazepam to terminate SE induced by lithium-pilocarpine (LiPilo-SE) or kainic acid (KA-SE) in 3-week-old rats was studied by video-electroencephalography.

Neurosteroid regulation of GABA receptors: A role in catamenial epilepsy.

The female reproductive hormones progesterone and estrogen regulate network excitability. Fluctuations in the circulating levels of these hormones during the menstrual cycle cause frequent seizures during certain phases of the cycle in women with epilepsy. This seizure exacerbation, called catamenial epilepsy, is a dominant form of drug-refractory epilepsy in women of reproductive age.

A novel therapeutic approach for treatment of catamenial epilepsy.

Many women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. There is no effective treatment for this condition, proposed to result from withdrawal of neurosteroid-mediated effects of progesterone. A double-blind, multicenter, phase III, clinical trial of catamenial epilepsy has failed to find a beneficial effect of progesterone.

Electroencephalography and behavior patterns during experimental status epilepticus.

Objective: To characterize the evolution of behavioral and electrographic seizures in an experimental electrical stimulation-based model of status epilepticus (SE) in C57Bl/6 mice, and to relate SE to various outcomes, including death and epileptogenesis.

Methods: SE was induced by continuous hippocampal stimulation and was evaluated by review of electroencephalographic recordings, spectral display, and behavior.

Results: Seizures were initially locked to the electrical trains but later became independent of them.

Neurosteroid-sensitive δ-GABA receptors: A role in epileptogenesis?

Objective: We determined the role of the neurosteroid-sensitive δ subunit-containing γ-aminobutyric acid A receptors (δ-GABARs) in epileptogenesis.

Methods: Status epilepticus (SE) was induced via lithium pilocarpine in adult rats, and seizures were assessed by continuous video-electroencephalography (EEG) monitoring. Finasteride was administered to inhibit neurosteroid synthesis.

Enhanced AMPA receptor-mediated neurotransmission on CA1 pyramidal neurons during status epilepticus.

Status epilepticus (SE) is a common neurological emergency that results from the failure of the mechanisms responsible for seizure termination or the initiation of mechanisms that lead to abnormally prolonged seizures. Although the failure of inhibitory mechanisms during SE is well understood, the seizure-initiating mechanisms are poorly understood. We tested whether hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission was enhanced during SE and assessed the underlying molecular mechanism.

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.