Abstracts

RATIONALE: We hypothesized that prolonged stimulation will reduce bicuculline-induced epileptiform activity (EA) by influencing neuronal/glial ionic currents leading to partial silencing of neural activity.
METHODS: Neuronal excitability (NE) in hippocampal neurons can be modulated and EA reduced by modifying ionic concentrations in the extracellular fluid. Specific patterns of stimulation might also be effective, but little is known about the effects of prolonged stimulation on NE and EA. Understanding mechanisms involved in prolonged stimulation has significance especially with the increased use of pacemakers for neurostimulation.
We used a rat hippocampal brain slice preparation to study changes in NE and EA induced by prolonged stimulation. Slices were prepared from approx. 28-32 day old rats (males) using standard methods (described previously). We stimulated (orthodromic) the Schaffer collaterals and recorded either excitatory post synaptic potentials (EPSPs) or population spike (PS) responses in the CA1 subfield. The criteria for healthy slices was determined by using only those slices that had PS responses that showed 2 mV or larger maximum amplitudes and that did not show multiple PSs under control and nontreated conditions. A baseline of 15 mins (test pulse at 0.034 Hz) was followed to evaluate response stability at half maximal intensity. Slices were then stimulated at either 1 or 100 Hz for either 1, 10, or 30 minutes. In some slices 200 uM bicuculline (GABA A antagonist) was applied after the establishment of baseline. After ten minutes of drug treatment, slices were stimulated (same as above). At the end of the stimulation period, we followed the responses for 20-30 minutes. We measured EPSP and PS responses (slope and amplitudes) and also evaluated potential spontaneous activity (between pulses) during baseline, drug treatment, stimulation, and post stimulation periods, unlike many investigators who only evaluate responses before and after stimulation.
RESULTS: We found that prolonged orthodromic stimulation (10 to 30 mins or more) at either 1 or 100 Hz is effective at reducing normal PS activity. PS responses appear to be more affected by stimulation protocols than EPSPs. We also found that bicuculline-induced EA (PS multiple spiking) is diminished by prolonged stimulation (1 or 100 Hz), where 1 Hz appears most effective. In this case the primary PS was reduced in amplitude and in some cases the additional PSs were either eliminated and/or reduced in size.
CONCLUSIONS: We conclude that the hippocampal brain slice technique can be used to isolate the effects of prolonged stimulation on neuronal properties and that selected stimulation paradigms can reduce NE and EA. We believe the results have significant relevance for investigators and clinicians trying to understand mechanisms associated with deep brain stimulation (DBS). These results further support the idea that investigational applications of DBS for epilepsy and seizure activity are warranted.
[Supported by: Berkeley Citizens Commission/Bayer Pharmaceuticals (BCA) and HL51614, NS43284, and NS38195 (DJ).]