Sodium butyrate enhances fear extinction and rescues hippocampal acetylcholinesterase activity in a rat model of posttraumatic stress disorder

Abstract

It is believed that impaired extinction of fear memories is an underlying cause for the development of posttraumatic stress disorder (PTSD). Histone deacetylases (HDAC) are enzymes that modulate extinction by changing the chromatin structure and altering protein synthesis in the brain. Studies show that stress modifies both HDAC activity and cerebral cholinergic neurotransmission. The present work aims to evaluate the effect of sodium butyrate (NaBu), an HDAC inhibitor, on behavioral markers of extinction and biochemical changes in HDAC and acetylcholinesterase activity in the hippocampus. NaBu was administered for 7 days in a group of rats that were exposed to single prolonged stress (SPS), as a model for PTSD. Contextual fear conditioning was performed on the 8th day, and fear extinction was measured in the next 4 consecutive days. Other behavioral tests to measure anxiety, locomotor activity and working memory were performed for further interpretation of the results. Hippocampal acetylcholinesterase and HDAC activity were also measured through biochemical tests. Behavioral results showed that treatment with NaBu can reverse the SPS-induced extinction deficits. Biochemical data indicated that while SPS induced overactivity in hippocampal HDAC, it decreased acetylcholinesterase activity in the region. Both effects were reversed after NaBu treatment. It seems that at least part of extinction deficiency in SPS exposed rats is related to hypoacetylation of acetylcholinesterase in the hippocampus. Preemptive therapy with an HDAC inhibitor reverses this process and is worth further evaluation as a possible therapeutic approach in PTSD.

Sex differences in acetylcholinesterase modulation during spatial and fear memory extinction in the amygdala; an animal study in the single prolonged stress model of PTSD

“…3A ). Cholinergic regulation through AchE modulation is reported in several other investigations( 21 36 37 38 ). We have recently found that reduced hippocampal cholinesterase activity occurs concurrently with extinction and working memory deficits( 36 ) in male rats.…”

“…Cholinergic regulation through AchE modulation is reported in several other investigations( 21 36 37 38 ). We have recently found that reduced hippocampal cholinesterase activity occurs concurrently with extinction and working memory deficits( 36 ) in male rats. The hippocampus receives cholinergic inputs from the medial septum and diagonal band of Broca neurons in the basal forebrain cholinergic nuclei, while the amygdala is innervated by neurons in the nucleus basalis magnocellularis.…”

Class I histone deacetylases inhibition reverses memory impairment induced by acute stress in mice

“…Histone deacetylation, mediated by HDACs enzymes, is a typical epigenetic regulatory mechanism involved in learning, memory formation, and stress [ 15 , 19 – 21 ]. In this regard, neuron-specific over-expression of HDAC2 impaired memory formation in adult mice, whereas HDAC2 deficiency resulted in memory facilitation, like that induced by nonselective HDACs inhibitors treatment [ 1 , 22 ].…”

Sodium butyrate exerts a neuroprotective effect in rats with acute carbon monoxide poisoning by activating autophagy through the mTOR signaling pathway

“…It has been shown that sodium butyrate prevents hypobaric hypoxia-induced spatial memory deficits 14 . In an animal model of posttraumatic stress disorder, sodium butyrate reversed single prolonged stress-induced hippocampal histone deacetylase (HDAC) overexpression and enhanced fear elimination 15 . Further, sodium butyrate improves synaptic plasticity by reducing neuroinflammation in 5XFAD mice early in the disease 16 .…”