Alterations in GABA receptor-mediated inhibition triggered by status epilepticus and their role in epileptogenesis and increased anxiety.

The triggers of status epilepticus (SE) in non-epileptic patients can vary widely, from idiopathic causes to exposure to chemoconvulsants. Regardless of its etiology, prolonged SE can cause significant brain damage, commonly resulting in the development of epilepsy, which is often accompanied by increased anxiety. GABA receptor (GABAR)-mediated inhibition has a central role among the mechanisms underlying brain damage and the ensuing epilepsy and anxiety.

Mechanisms of Organophosphate Toxicity and the Role of Acetylcholinesterase Inhibition.

Organophosphorus compounds (OPs) have applications in agriculture (e.g., pesticides), industry (e.

Preventing Long-Term Brain Damage by Nerve Agent-Induced Status Epilepticus in Rat Models Applicable to Infants: Significant Neuroprotection by Tezampanel Combined with Caramiphen but Not by Midazolam Treatment.

Acute exposure to nerve agents induces a peripheral cholinergic crisis and prolonged status epilepticus (SE), causing death or long-term brain damage. To provide preclinical data pertinent to the protection of infants and newborns, we compared the antiseizure and neuroprotective effects of treating soman-induced SE with midazolam (MDZ) versus tezampanel (LY293558) in combination with caramiphen (CRM) in 12- and 7-day-old rats. The anticonvulsants were administered 1 hour after soman exposure; neuropathology data were collected up to 6 months postexposure.

Alpha-linolenic acid enhances the facilitation of GABAergic neurotransmission in the BLA and CA1.

Hyperexcitability is a major mechanism implicated in several neuropsychiatric disorders, such as organophosphate-induced status epilepticus (SE), primary epilepsy, stroke, spinal cord injury, traumatic brain injury, schizophrenia, and autism spectrum disorders. Underlying mechanisms are diverse, but a functional impairment and loss of GABAergic inhibitory neurons are common features in many of these disorders. While novel therapies abound to correct for the loss of GABAergic inhibitory neurons, it has been difficult at best to improve the activities of daily living for the majority of patients.

Antiseizure and Neuroprotective Efficacy of Midazolam in Comparison with Tezampanel (LY293558) against Soman-Induced Status Epilepticus.

Acute exposure to nerve agents induces status epilepticus (SE), which can cause death or long-term brain damage. Diazepam is approved by the FDA for the treatment of nerve agent-induced SE, and midazolam (MDZ) is currently under consideration to replace diazepam. However, animal studies have raised questions about the neuroprotective efficacy of benzodiazepines.

Increased inhibitory activity in the basolateral amygdala and decreased anxiety during estrus: A potential role for ASIC1a channels.

The amygdala is central to emotional behavior, and the excitability level of the basolateral nucleus of the amygdala (BLA) is associated with the level of anxiety. The excitability of neuronal networks is significantly controlled by GABAergic inhibition. Here, we investigated whether GABAergic inhibition in the BLA is altered during the rat estrous cycle.

The Recovery of GABAergic Function in the Hippocampus CA1 Region After mTBI.

Traumatic brain injury (TBI) is a major public health concern in the USA. There are approximately 2.5 million brain injuries annually, 90% of which may be classified as mild since these individuals do not display clear morphological abnormalities following injury on imaging.

Comparing the Antiseizure and Neuroprotective Efficacy of LY293558, Diazepam, Caramiphen, and LY293558-Caramiphen Combination against Soman in a Rat Model Relevant to the Pediatric Population.

The currently Food and Drug Administration-approved anticonvulsant for the treatment of status epilepticus (SE) induced by nerve agents is the benzodiazepine diazepam; however, diazepam does not appear to offer neuroprotective benefits. This is of particular concern with respect to the protection of children because, in the developing brain, synaptic transmission mediated via GABA receptors, the target of diazepam, is weak. In the present study, we exposed 21-day-old male rats to 1.

Oscillatory Synchronous Inhibition in the Basolateral Amygdala and its Primary Dependence on NR2A-containing NMDA Receptors.

Synchronous, rhythmic firing of GABAergic interneurons is a fundamental mechanism underlying the generation of brain oscillations, and evidence suggests that NMDA receptors (NMDARs) play a key role in oscillatory activity by regulating the activity of interneurons. Consistent with this, derangement of brain rhythms in certain neuropsychiatric disorders, notably schizophrenia and autism, is associated with NMDAR hypofunction and loss of inhibitory interneurons. In the basolateral amygdala (BLA)-dysfunction of which is involved in a host of neuropsychiatric diseases-, principal neurons display spontaneous, rhythmic "bursts" of inhibitory activity, which could potentially be involved in the orchestration of oscillations in the BLA network; here, we investigated the role of NMDARs in these inhibitory oscillations.

Alpha-Linolenic Acid Treatment Reduces the Contusion and Prevents the Development of Anxiety-Like Behavior Induced by a Mild Traumatic Brain Injury in Rats.

Approximately, 1.7 million Americans suffer a TBI annually and TBI is a major cause of death and disability. The majority of the TBI cases are of the mild type and while most patients recover completely from mild TBI (mTBI) about 10% result in persistent symptoms and some result in lifelong disability.

The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala.

Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure.

Repeated Isoflurane Exposures Impair Long-Term Potentiation and Increase Basal GABAergic Activity in the Basolateral Amygdala.

After surgery requiring general anesthesia, patients often experience emotional disturbances, but it is unclear if this is due to anesthetic exposure. In the present study, we examined whether isoflurane anesthesia produces long-term pathophysiological alterations in the basolateral amygdala (BLA), a brain region that plays a central role in emotional behavior. Ten-week-old, male rats were administered either a single, 1 h long isoflurane (1.

GABAergic interneuronal loss and reduced inhibitory synaptic transmission in the hippocampal CA1 region after mild traumatic brain injury.

Patients that suffer mild traumatic brain injuries (mTBI) often develop cognitive impairments, including memory and learning deficits. The hippocampus shows a high susceptibility to mTBI-induced damage due to its anatomical localization and has been implicated in cognitive and neurological impairments after mTBI. However, it remains unknown whether mTBI cognitive impairments are a result of morphological and pathophysiological alterations occurring in the CA1 hippocampal region.

Pathophysiological mechanisms underlying increased anxiety after soman exposure: reduced GABAergic inhibition in the basolateral amygdala.

The recent sarin attack in Syria killed 1429 people, including 426 children, and left countless more to deal with the health consequences of the exposure. Prior to the Syrian chemical assault, nerve agent attacks in Japan left many victims suffering from neuropsychiatric illnesses, particularly anxiety disorders, more than a decade later. Uncovering the neuro-pathophysiological mechanisms underlying the development of anxiety after nerve agent exposure is necessary for successful treatment.

Reduced GABAergic inhibition in the basolateral amygdala and the development of anxiety-like behaviors after mild traumatic brain injury.

Traumatic brain injury (TBI) is a major public health concern affecting a large number of athletes and military personnel. Individuals suffering from a TBI risk developing anxiety disorders, yet the pathophysiological alterations that result in the development of anxiety disorders have not yet been identified. One region often damaged by a TBI is the basolateral amygdala (BLA); hyperactivity within the BLA is associated with increased expression of anxiety and fear, yet the functional alterations that lead to BLA hyperexcitability after TBI have not been identified.

ASIC1a activation enhances inhibition in the basolateral amygdala and reduces anxiety.

The discovery that even small changes in extracellular acidity can alter the excitability of neuronal networks via activation of acid-sensing ion channels (ASICs) could have therapeutic application in a host of neurological and psychiatric illnesses. Recent evidence suggests that activation of ASIC1a, a subtype of ASICs that is widely distributed in the brain, is necessary for the expression of fear and anxiety. Antagonists of ASIC1a, therefore, have been proposed as a potential treatment for anxiety.

α7-Containing nicotinic acetylcholine receptors on interneurons of the basolateral amygdala and their role in the regulation of the network excitability.

The basolateral amygdala (BLA) plays a key role in fear-related learning and memory, in the modulation of cognitive functions, and in the overall regulation of emotional behavior. Pathophysiological alterations involving hyperexcitability in this brain region underlie anxiety and other emotional disorders as well as some forms of epilepsy. GABAergic interneurons exert a tight inhibitory control over the BLA network; understanding the mechanisms that regulate their activity is necessary for understanding physiological and disordered BLA functions.

Presynaptic facilitation of glutamate release in the basolateral amygdala: a mechanism for the anxiogenic and seizurogenic function of GluK1 receptors.

Kainate receptors containing the GluK1 subunit (GluK1Rs; previously known as GluR5 kainate receptors) are concentrated in certain brain regions, where they play a prominent role in the regulation of neuronal excitability, by modulating GABAergic and/or glutamatergic synaptic transmission. In the basolateral nucleus of the amygdala (BLA), which plays a central role in anxiety as well as in seizure generation, GluK1Rs modulate GABAergic inhibition via postsynaptic and presynaptic mechanisms. However, the role of these receptors in the regulation of glutamate release, and the net effect of their activation on the excitability of the BLA network are not well understood.

Neuroprotective efficacy of caramiphen against soman and mechanisms of its action.

Background And Purpose: Caramiphen is a muscarinic antagonist with potent anticonvulsant properties. Here, we investigated the efficacy of caramiphen against behavioural seizures and neuropathology induced by the nerve agent soman, and revealed two mechanisms that may underlie the anticonvulsant efficacy of caramiphen.

Experimental Approach: Rats were given caramiphen at 30 or 60 min after treatment with soman.

RDX binds to the GABA(A) receptor-convulsant site and blocks GABA(A) receptor-mediated currents in the amygdala: a mechanism for RDX-induced seizures.

Background: Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a high-energy, trinitrated cyclic compound that has been used worldwide since World War II as an explosive in both military and civilian applications. RDX can be released in the environment by way of waste streams generated during the manufacture, use, and disposal of RDX-containing munitions and can leach into groundwater from unexploded munitions found on training ranges. For > 60 years, it has been known that exposure to high doses of RDX causes generalized seizures, but the mechanism has remained unknown.

Addictive nicotine alters local circuit inhibition during the induction of in vivo hippocampal synaptic potentiation.

The drug addiction process shares many commonalities with normal learning and memory. Addictive drugs subvert normal synaptic plasticity mechanisms, and the consequent synaptic changes underlie long-lasting modifications in behavior that accrue during the progression from drug use to addiction. Supporting this hypothesis, it was recently shown that nicotine administered to freely moving mice induces long-term synaptic potentiation of the perforant path connection to granule cells of the dentate gyrus.

Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage.

Acid-sensitive ion channels (ASICs) are proton-gated and belong to the family of degenerin channels. In the mammalian nervous system, ASICs are most well known in sensory neurons, where they are involved in nociception, occurring when injury or inflammation causes acidification. ASICs also are widely expressed in the CNS, and some synaptic roles have been revealed.

Applying small quantities of multiple compounds to defined locations of in vitro brain slices.

When studying in vitro brain slices, rapidly applying multiple agonists, antagonists, drugs, or modulatory compounds is a significant technical problem. There are three major ways that multiple compounds are applied to slices: by bath, via a U-tube device, or by pressure application using a "puffer" pipette. Each of these methods has advantages and disadvantages, making each more appropriate for particular purposes.

Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction.

Tobacco use is a major health problem that is estimated to cause 4 million deaths a year worldwide. Nicotine is the main addictive component of tobacco. It acts as an agonist to activate and desensitize nicotinic acetylcholine receptors (nAChRs).