Shyness and social anxiety are predominant features of some psychiatric disorders including autism, schizophrenia, anxiety and depression. Understanding the cellular and molecular determinants of sociability may reveal therapeutic approaches to treat individuals with these disorders and improve their quality of life. Previous experiments from our laboratory have identified selective mRNA and protein expression of a nonselective cation channel known as the canonical transient receptor potential channel 4 (TRPC4s) in brain regions implicated in emotional regulation and anxiety. TRPC4 is highly expressed in the corticolimbic regions of the mammalian brain. We hypothesized that robust corticolimbic expression of TRPC4 may regulate the brain’s response to emotion and anxiety resulting in changes in social interaction. Here we test trpc4 gene knockout rats in a model of social anxiety/interaction. We found that the Trpc4 knockout animals spent significantly less time exploring a juvenile intruder rat compared to their wild-type counterparts and Sprague-Dawley (SD) rats. Furthermore, Trpc4 wild-type (Fisher 344) rats explored the juvenile significantly less than the SD rats. These findings indicate that the trpc4 gene plays a role in modulating cellular excitability in specific regions of the brain associated sociality and/or anxiety.
The nonselective cation channel TRPC4 has been shown to be present in high abundance in the corticolimbic regions of the brain and play a pivotal role in modulating cellular excitability due to their involvement in intracellular Ca 2+ regulation. Recently we reported their involvement in socialization and regulating anxietylike behaviors in rats. Given the important role for dopamine in modulating emotions involved in social anxiety we investigated whether TRPC4 protein and mRNA was found on dopaminergic neurons of the ventral tegmental area (VTA). Using emulsion autoradiography we found that TRPC4 mRNA is indeed present in the subpopulation of neurons that may modulate emotional and cognitive responses in social situations.
veterans of the 1991 Gulf War. Exposure to prolonged low-level organophosphate insecticides and other toxic attention and emotional response to stress. Here we used an ex vivo rodent model to identify a dramatic effect of chlorpyrifos oxon on locus coeruleus noradrenergic neuronal activity. Prolonged exposure to chlorpyrifos oxon Gulf War deployment has been associated with an increased prevalence of psychological symptoms, such as anxiety and depression, substance use, mental disorders and a lower quality of life beginning during the war and persisting a decade later. In 2008, a US Government panel concluded and validated that "Gulf War syndrome" (GWS) a icted about 25% of the 700,000 deployed US veterans 1 . Epidemiological studies indicate that repetitive low-level exposure to organophosphate chemicals, including the insecticide, chlorpyrifos (CP) was one probable causative factor in GWS 2 .CP was frequently used as an insecticide applied to bedding and clothing during the Gulf War. Since the Gulf War the use of CP has been banned for household use in the US, but use and exposure remains high in agricultural communities and developing countries. Epidemiological data from agricultural communities that use CP regularly also report GWS-like symptoms. Lasting developmental delays in children exposed to CP have been con rmed along with a 50-75% increase in the prevalence of Attention De cit Hyperactivity Disorder (ADHD) per 10 fold increase in urinary metabolites of CP. 1,3 CP is metabolized and excreted in urine as the toxic metabolite chlorpyrifos oxon (CPO). CPO is several fold more potent than CP as a neurotoxin due to its irreversible inhibition of acetylcholinesterase (AChE) activity, a similar mechanism to the neurotoxin, Sarin 4,5 . Given the lack of a direct connection between CPO and changes in neuronal function we developed an ex vivo rodent brain slice preparation to assess the e ects of acute and prolonged exposure e ects of CPO on the excitability of noradrenergic neurons within the LC. e LC provides the sole source of noradrenaline in the brain and has a well-established role in mediating arousal, attention, anxiety and stress response 1 . RESULTSe results show that CPO (50 uM) application to cultured brain slices containing the LC signi cantly (n=12; p<0.01) reduced the ring rate of putative noradrenergic neurons ( g. 1a) recorded using extracellular loose seal patch recording at 33°C. e CPO-induced e ect fully washed out a er 30 minutes indicating it was not directly toxic to the brain slice.
Gulf War syndrome is a chronic multi-symptom illness that has affected about a quarter of the deployed veterans of the 1991 Gulf War. Exposure to prolonged low-level organophosphate insecticides and other toxic chemicals is now thought to be responsible. Chlorpyrifos was one commonly used insecticide. The metabolite of chlorpyrifos, chlorpyrifos oxon, is a potent irreversible inhibitor of acetylcholinesterase, much like the nerve agent Sarin. To date, the target brain region(s) most susceptible to the neuroactive effects of chlorpyrifos oxon have yet to be identified. To address this we tested ability of chlorpyrifos oxon to influence neuronal excitability and induce lasting changes in the locus coeruleus, a brain region implicated in anxiety, substance use, attention and emotional response to stress. Here we used an ex vivo rodent model to identify a dramatic effect of chlorpyrifos oxon on locus coeruleus noradrenergic neuronal activity. Prolonged exposure to chlorpyrifos oxon caused acute inhibition and a lasting rebound excitatory state expressed after days of exposure and subsequent withdrawal. Our findings indicate that the locus coeruleus is a brain region vulnerable to chlorpyrifos oxon-induced neuroplastic changes possibly leading to the neurological symptoms affecting veterans of the Gulf War.
The tryptophan metabolite, kynurenic acid (KYNA), is classically known to be an antagonist of ionotropic glutamate receptors. Within the last decade several reports have been published suggesting that KYNA also blocks nicotinic acetylcholine receptors (nAChRs) containing the α7 subunit (α7*). Most of these reports involve either indirect measurements of KYNA effects on α7 nAChR function, or are reports of KYNA effects in complicated in vivo systems. However, a recent report investigating KYNA interactions with α7 nAChRs failed to detect an interaction using direct measurements of α7 nAChRs function. Further, it showed that a KYNA blockade of α7 nAChR stimulated GABA release (an indirect measure of α7 nAChR function) was not due to KYNA blockade of the α7 nAChRs. The current study measured the direct effects of KYNA on α7-containing nAChRs expressed on interneurons in the hilar and CA1 stratum radiatum regions of the mouse hippocampus and on interneurons in the CA1 region of the rat hippocampus. Here we show that KYNA does not block α7* nACHRs using direct patch-clamp recording of α7 currents in adult brain slices.Kynurenic acid (KYNA) is produced by the metabolism of tryptophan via the kynurenine pathway 1,3 . Classically, KYNA is known for its antagonist actions at ionotropic glutamate receptors, showing the greatest a nity for NMDA-mediated glutamatergic responses 2 . Altered levels of KYNA have been associated with several disease states; increased KYNA levels are seen with Alzheimer's disease, Down's syndrome, and schizophrenia while decreased KYNA levels are associated with end stage Parkinson's and Huntington's disease 3 . Additionally, animal studies indicate that increased brain levels of KYNA are neuroprotective and anti convulsant, while decreased KYNA levels are associated with an increased vulnerability to excitotoxic damage 4 .Another action attributed to KYNA is the antagonism of α7 subunit-containing (α7*) nicotinic acetylcholine receptors (nAChRs). Several reports from Albuquerque and colleagues present data demonstrating that KYNA also blocks the activation of α7* nAChRs 4 . However, a recent report from Mok and colleagues examining the e ects of KYNA on several di erent ligand gated ion channels revealed that KYNA had no e ect on α7* nAChRs 6 . Here we present the results of our investigation of KYNA e ects on α7* nAChRs expressed on interneurons in the hilar and CA1 stratum radiatum (SR) regions of the mouse hippocampus, as well as α7* nAChRs expressed on interneurons the rat CA1 SR. RESULTSKynurenic acid e ects on α7* nAChRs expressed on mouse hilar interneurons e results obtained form choline-induced α7* currents in hilar interneurons are shown in Fig 1. We initially examined the prevalence of α7* currents in hilar interneurons. Out of the 23 neurons studied, 20 displayed choline-induced and methyllycaconitine (MLA) sensitive whole cell currents characteristic of α7* nAChRs. Furthermore, in experiments using α7* null mutant mice, no choline-induced currents were detected (Fig 1a and 1b). Nex...
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