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

Abstract

The recent sarin attack in Syria killed 1,429 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. Anxiety is associated with hyperexcitability of the basolateral amygdala (BLA). The present study sought to determine the nature of the nerve agent-induced alterations in the BLA, which could explain the development of anxiety. Rats were exposed to soman, at a dose that induced prolonged status epilepticus. Twenty-four hours and 14-days after exposure, neurons from the BLA were recorded using whole-cell patch-clamp techniques. At both the 24 h and 14-day post-exposure time-points, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in the BLA were reduced, along with reduction in the frequency but not amplitude of miniature IPSCs. In addition, activation of α7-nicotinic acetylcholine receptors, a cholinergic receptor that participates in the regulation of BLA excitability and is involved in anxiety, increased spontaneous excitatory postsynaptic currents (sEPSCs) in both soman-exposed rats and controls, but was less effective in increasing sIPSCs in soman-exposed rats. Despite the loss of both interneurons and principal cells after soman-induced status epilepticus, the frequency of sEPSCs was increased in the soman-exposed rats. Impaired function and cholinergic modulation of GABAergic inhibition in the BLA may underlie anxiety disorders that develop after nerve agent exposure.

Genetic deletion of monoacylglycerol lipase leads to impaired cannabinoid receptor CB1R signaling and anxiety‐like behavior

“…Indeed, by using microdialysis we found increased extracellular glutamate levels in the mPFC of MAGLÀ/À mice, and this observation provided direct evidence of increased of excitatory drive in the PFCpyramidal circuitry. Also alterations in GABAergic transmission in the amygdala play a key role in the etiology of anxiety-like behaviors (Prager et al 2014) and, indeed, animal models of anxiety show increased VGAT expression (Inta et al 2012). Accordingly, we observed a significant increase in VGAT immunodensity in the BLA.…”

“…Impairment of CB 1 R signaling affects the neuronal excitatory/inhibitory balance with effects on emotional function and anxiety-or depressive-like behaviors (Chiba et al 2012;den Boon et al 2014;Prager et al 2014). Anxiety can be modulated by eCB in a bimodal way through the activation of different subsets of CB 1 R at excitatory/ VGluT1-or inhibitory/VGAT-positive inputs (Ruehle et al 2012), which, in turn, can affect the VGluT1 or VGAT presynaptic density and their vesicular quantal size (Daniels et al 2004;Wilson et al 2005).…”

“…Anxiety can be modulated by eCB in a bimodal way through the activation of different subsets of CB 1 R at excitatory/ VGluT1-or inhibitory/VGAT-positive inputs (Ruehle et al 2012), which, in turn, can affect the VGluT1 or VGAT presynaptic density and their vesicular quantal size (Daniels et al 2004;Wilson et al 2005). These alterations play a key role in the etiology of anxiety-like behaviors when occurring in PFC, amygdala and hippocampal circuits (Chiba et al 2012;Prager et al 2014).…”

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

“…GABAergic control of the excitability of the BLA network appears to be particularly powerful (Rainnie, 1999;Muller et al, 2005;Pan et al, 2009;Popescu and Pare, 2011), and we have shown previously that it is severely compromised after exposure to soman (Prager et al, 2014b), along with an increase in anxiety-like behavior (Prager et al, 2014a). Therefore, in the present study, we compared the efficacy of the anticonvulsant treatments in preventing the decrease in spontaneous inhibitory activity caused by soman exposure.…”

Anti-glutamic acid decarboxylase antibody positive neurological syndromes

“…It decreases neuronal excitability in the brain and plays an important role in muscle tone regulation 1. It is produced by cells in the nervous system known as GABAergic neurons that have an inhibitory action at receptors in an adult human or animal 2,3. In addition to inhibition, some GABAergic neurons, such as chandelier cells, are also capable of exciting their glutamatergic counterparts 4.…”