Book excerpt: Organophosphates (OPs) are a group of synthetic compounds that are estimated to be responsible for millions of accidental or intentional human poisonings each year. The canonical mechanism of OP neurotoxicity is inhibition of acetylcholinesterase (AChE); however, multiple lines of evidence suggest that mechanisms in addition to or other than AChE inhibition contribute to the long-term effects associated with acute OP intoxication. It is important to study these pathogenic mechanisms in order to ultimately improve the current standard of care for survivors of acute OP intoxication. The use of preclinical animal models that recapitulate the human condition have been essential for studying the neurologic sequelae following OP poisoning; however, the heterogeneity of responses to different OP compounds suggest that a more thorough characterization of these models is required. In chapter 2, we took advantage of a rodent model of acute intoxication with the OP pesticide, diisopropylfluorophosphate (DFP), to identify that persistent microgliosis, astrogliosis, and oxidative stress responses occur in the same animals with cognitive deficits, affective-like disorders, and acquired epilepsy. Together, these studies highlight potential pathogenic mechanisms that may underlie these behavioral impairments. However, few published studies have reported on the efficacy of therapeutic compounds that target these pathways in reducing long-term behavioral morbidities following acute OP intoxication. Therefore, in chapter 4 we screened twelve pharmacologically distinct compounds for therapeutic potential in reducing OP-induced neurodegeneration and neuroinflammation. We identified compounds with anti-inflammatory properties were the most effective at reducing metrics of microglial activation at 7 days post-DFP, as determined by a self-developed, automated tool (outlined in chapter 3). Furthermore, we determined that daily treatment with minocycline, an FDA-approved tetracycline antibiotic with microglial inhibitory properties, reduced the severity of acquired epilepsy for one month following DFP. These studies suggest that neuroinflammatory mechanisms are likely involved in epileptogenesis following acute OP intoxication and highlight possible therapeutic targets that should be further investigated with the hopes of identifying improved medical countermeasures for survivors of acute OP intoxication.