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Although there has been an increasing appreciation for functional differences between the dorsal (dH) and ventral (vH) hippocampal sectors, there is a lack of information characterizing the cholinergic and noncholinergic mechanisms of acetylcholinesterase inhibitors on synaptic transmission along the hippocampal dorsoventral axis. Diisopropylfluorophosphate (DFP) is an organophosphate (OP) that is commonly employed as a nerve agent surrogate in vitro as well as in rodent models of disease states, such as Gulf War Illness. The present study investigated the cholinergic and noncholinergic mechanisms responsible for the effects of acute DFP exposure on dH and vH synaptic transmission in a hippocampal slice preparation. A paired-pulse extracellular recording protocol was used to monitor the population spike (PS) amplitude as well as the PS paired-pulse ratio (PS-PPR) in the CA1 subfield of the dH and the vH. We observed that DFP-induced PS1 inhibition was produced by a cholinergic mechanism in the dH, whereas a noncholinergic mechanism was indispensable in mediating the inhibitory effect of DFP on the PS1 in the vH. PS-PPR in both dH and vH sectors was increased by acute DFP exposure, an effect that was blocked by an N-methyl-D-aspartate receptor antagonist but not by cholinergic antagonists. Clinical reports have indicated dorsoventral-specific hippocampal abnormalities in cases of OP intoxications. Therefore, the observed dorsoventral-specific noncholinergic mechanisms underlying the effects of DFP on hippocampal synaptic transmission may have important implications for the treatment of OP overexposures. SIGNIFICANCE STATEMENT: It is unknown if acetylcholinesterase inhibitors differentially impact dorsal and ventral hippocampal synaptic transmission. The data in the present study show that an organophosphate, diisopropylfluorophosphate, impacts glutamatergic transmission along the dorsoventral axis in a hippocampal slice preparation via distinct cholinergic and noncholinergic mechanisms. These findings may provide insight into investigations of therapeutic agents that target noncholinergic mechanisms in cases of organophosphate overexposures.

Dorsoventral-Specific Effects of Nerve Agent Surrogate Diisopropylfluorophosphate on Synaptic Transmission in the Mouse Hippocampus