title: Pyrethroid modulation of spontaneous neuronal excitability and neurotransmission in hippocampal neurons in culture.
abstract: Pyrethroid insecticides have potent actions on voltage-gated sodium channels (VGSC), inhibiting inactivation and increasing channel open times. These are thought to underlie, at least in part, the clinical symptoms of pyrethroid intoxication. However, disruption of neuronal activity at higher levels of organization is less well understood. In order to characterize pyrethroid effects on neurotransmitter release and neuronal excitability in glutamatergic networks, we examined the effects of deltamethrin (DM) and permethrin (PM) on neuronal activity in hippocampal neuronal cultures using patch-clamp and microelectrode array (MEA) recordings. In the presence of inhibitors of GABA receptors, spontaneous excitatory post-synaptic currents (sEPSCs) and spontaneous spike rates were reduced in a concentration-dependent manner by both DM and PM. IC(50) values were 0.037 and 0.70microM for inhibition of sEPSCs and 0.60 and 21.8microM for inhibition of spontaneous spike rate by DM and PM, respectively. Both compounds altered burst activity by decreasing the number of spikes during spontaneous bursting, the number of sEPSCs within a bursting release event and the duration of sEPSC bursts while increasing both the interspike interval and the time between sEPSCs. Exposure of neurons to the VGSC-specific modulator veratridine had effects similar to both DM and PM, while inhibition of voltage-gated calcium channels had no effect on spontaneous spike rates. In the absence of GABA receptor antagonists, both DM and PM increased spontaneous spike rates. Altogether, these data demonstrate that DM and PM disrupt network activity in vitro, largely via a VGSC-dependent mechanism.
authors.affiliation: Curriculum in Toxicology, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Meyer
authors.forename: Julianne M
authors.initials: JM
authors.lastname: Carter
authors.forename: Andrew F M
authors.initials: AF
authors.lastname: Johnstone
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Shafer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D049990:Membrane Transport Modulators / Q000494:pharmacology; D046228:Microarray Analysis; D008839:Microelectrodes; D009415:Nerve Net / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009570:Nitriles / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D026023:Permethrin / Q000633:toxicity*; D011722:Pyrethrins / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors; D014701:Veratridine / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007306:Insecticides; D049990:Membrane Transport Modulators; D009570:Nitriles; D011722:Pyrethrins; D015222:Sodium Channels; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; C017180:decamethrin; D018698:Glutamic Acid; D026023:Permethrin; D014701:Veratridine