Neonatal exposure to low-dose domoic acid lowers seizure threshold in adult rats

Abstract

Exposing Sprague–Dawley rat pups to very low, sub-convulsant doses of domoic acid (DOM) during perinatal development has been previously shown to result in seizure-like activity in adulthood similar to partial complex epilepsy in humans, and to produce cellular and molecular changes in the dentate gyrus and area CA-3 of the hippocampus. To further these investigations we recorded electroencephalographical and behavioural activity in DOM and control rats following a normally sub-convulsant dose (25 mg/kg) of pentylenetetrazol. During this exposure, 50% of DOM-treated rats experienced a Stage V (tonic-clonic) seizure (X2(1)=5.33, P=0.021), indicating a lowering of generalized seizure threshold in these animals. In a separate experiment we explored focal seizure (afterdischarge) threshold as well as seizure propagation rates in treated rats, using a 25 consecutive day standard amygdala kindling paradigm. We report that the afterdischarge threshold for DOM-treated rats was significantly lower than controls (F(1,27)=7.117, P=0.013). No difference between groups was found in seizure progression as measured by afterdischarge duration, latency to first Stage V seizure, or latency to reach a fully kindled state (defined as five consecutive Stage V seizures). Timm staining to assess mossy fibre sprouting (MFS) in the hippocampus revealed a significant MFS increase relative to sham at the ventral level in both left and right inner molecular layer of the dentate gyrus for all DOM-treated animals, as well as in the dorsal stratum oriens of CA3 contralateral to electrode placement, and these increases were further enhanced by the kindling procedure. We conclude that perinatal exposure to subconvulsive doses of DOM results in permanent changes in neuronal excitability in the adult rat, as demonstrated by a lowering of both generalized seizure and focal afterdischarge threshold, and produces increased MFS following kindling.