Abnormal neurotransmission of GABA and serotonin in Caenorhabditis elegans induced by Fumonisin B1.

Fumonisin B1 (FB1) is a neurodegenerative mycotoxin synthesized by Fusarium spp., but the potential neurobehavioral toxicity effects in organisms have not been characterized clearly. Caenorhabditis elegans (C. elegans) has emerged as a promising model organism for neurotoxicological studies due to characteristics such as well-functioning nervous system and rich behavioral phenotypes. To investigate whether FB1 has neurobehavioral toxicity effects on C. elegans, the motor behavior, neuronal structure, neurotransmitter content, and gene expression related with neurotransmission of C. elegans were determined after exposed to 20-200 µg/mL FB1 for 24 h and 48 h, respectively. Results showed that FB1 caused behavioral defects, including body bends, head thrashes, crawling distance, mean speed, mean amplitude, mean wavelength, foraging behavior, and chemotaxis learning ability in a dose-, and time-dependent manner. In addition, when C. elegans was exposed to FB1 at a concentration of 200 µg/mL for 24 h and above 100 µg/mL for 48 h, the GABAergic and serotonergic neurons were damaged, but no effect on dopaminergic, glutamatergic, and cholinergic neurons. The relative content of GABA and serotonin decreased significantly. Furthermore, abnormal expression of mRNA levels associated with GABA and serotonin were found in nematodes treated with FB1, such as unc-30, unc-47, unc-49, exp-1, mod-5, cat-1, and tph-1. The neurobehavioral toxicity effect of FB1 may be mediated by abnormal neurotransmission of GABA and serotonin. This study provides useful information for understanding the neurotoxicity of FB1.

Partial TrkB receptor activation suppresses cortical epileptogenesis through actions on parvalbumin interneurons.

Post-traumatic epilepsy is one of the most common and difficult to treat forms of acquired epilepsy worldwide. Currently, there is no effective way to prevent post-traumatic epileptogenesis. It is known that abnormalities of interneurons, particularly parvalbumin-containing interneurons, play a critical role in epileptogenesis following traumatic brain injury. Thus, enhancing the function of existing parvalbumin interneurons might provide a logical therapeutic approach to prevention of post-traumatic epilepsy. The known positive effects of brain-derived neurotrophic factor on interneuronal growth and function through activation of its receptor tropomyosin receptor kinase B, and its decrease after traumatic brain injury, led us to hypothesize that enhancing trophic support might improve parvalbumin interneuronal function and decrease epileptogenesis. To test this hypothesis, we used the partial neocortical isolation ('undercut', UC) model of posttraumatic epileptogenesis in mature rats that were treated for 2 weeks, beginning on the day of injury, with LM22A-4, a newly designed partial agonist at the tropomyosin receptor kinase B. Effects of treatment were assessed with Western blots to measure pAKT/AKT; immunocytochemistry and whole cell patch clamp recordings to examine functional and structural properties of GABAergic interneurons; field potential recordings of epileptiform discharges in vitro; and video-EEG recordings of PTZ-induced seizures in vivo. Results showed that LM22A-4 treatment 1) increased pyramidal cell perisomatic immunoreactivity for VGAT, GAD65 and parvalbumin; 2) increased the density of close appositions of VGAT/gephyrin immunoreactive puncta (putative inhibitory synapses) on pyramidal cell somata; 3) increased the frequency of mIPSCs in pyramidal cells; and 4) decreased the incidence of spontaneous and evoked epileptiform discharges in vitro. 5) Treatment of rats with PTX BD4-3, another partial TrkB receptor agonist, reduced the incidence of bicuculline-induced ictal episodes in vitro and PTZ induced electrographic and behavioral ictal episodes in vivo. 6) Inactivation of TrkB receptors in undercut TrkBF616A mice with 1NMPP1 abolished both LM22A-4-induced effects on mIPSCs and on increased perisomatic VGAT-IR. Results indicate that chronic activation of the tropomyosin receptor kinase B by a partial agonist after cortical injury can enhance structural and functional measures of GABAergic inhibition and suppress posttraumatic epileptogenesis. Although the full agonist effects of brain-derived neurotrophic factor and tropomyosin receptor kinase B activation in epilepsy models have been controversial, the present results indicate that such trophic activation by a partial agonist may potentially serve as an effective therapeutic option for prophylactic treatment of posttraumatic epileptogenesis, and treatment of other neurological and psychiatric disorders whose pathogenesis involves impaired parvalbumin interneuronal function.