mGluR 2/3 agonist DCG-IV Increases the Epileptiform Threshold in Rat Hippocampal Dentate Gyrus Brain Slices

Undergraduate #125
Discipline: Biological Sciences
Subcategory: Physiology and Health

Gerardo Rodriguez-Orellana - University of Utah
Co-Author(s): Brandon Wright and Meyer Jackson, University of Wisconsin-Madison, Madison, WI

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Mounting evidence suggests that hippocampal dysfunction plays a critical role in the pathology of epilepsy, possibly due to the excitatory feedback found in this region. The dentate gyrus (DG) within the hippocampus receives the strongest input of the hippocampus. Over-activation of this region can initiate epileptiform activity, which could extend to other regions if the inhibitory barrier is broken down. This circuit is composed of three neuronal subtypes. Granule cells (GCs), the primary cells of the HDG, are kept mostly quiescent by mossy cells (MCs) and interneurons. MCs innervate GCs near the granule cell somata. MCs and interneurons have higher sensitivity to electrical stimulation than GCs. Through the induction protocol (2 Hz for 1 h) and changes in the environment (increased potassium and reduced concentration of magnesium), inhibition of GCs by MCs and interneurons can be diminished and lead to epileptiform activity. We are interested in controlling this epileptiform activity through pharmacological means. Here, we suppress glutamate release from GCs through the application of an mGluR 2/3 agonist (DCG-IV) at a concentration of 1μM in order to observe its efficiency in suppressing epileptiform activity.

After the induction protocol was applied, it was clear the reduction of inhibitory barriers rendering the slice hyperexcitable. It was also noticed that the time for the population response to peak was faster than the controls. After the application of DCG-IV, hyper-excitability could not be induced in the tissue due to an increase in the epileptiform threshold but the time between stimulus and population response maintained constant. The experiments showed that the electrical induction protocol successfully induces epileptiform activity by suppressing inhibitory barriers by suppressing the MCs. It also demonstrated that DCG-IV does alter some aspects of epileptiform activity. More specifically, at a concentration of 1μM DCG-IV reduces the amplitude of the population response after the induction protocol. This is consistent with previous studies that have demonstrated that DCG-IV reduces the field excitatory postsynaptic potentials, decreasing the overall response. However, due to the fact that the inhibitory barriers had been suppressed by the induction protocol, DCG-IV had no effect on the speed of the response. This research has allowed insight into the effects of DCG-IV on hyper-excitable tissue, such as increasing the threshold for epileptiform activity and suppressing the complexity of the population responses. It also demonstrated that DCG-IV has no effect on the response time between the stimulation and the population response. Possible future directions to explore include the investigation of various concentrations of DCG-IV on hyper-excitable tissue as well as investigating these physiological effects through Voltage Imaging techniques.

Funder Acknowledgement(s): National Science Foundation (DBI -1063085), University of Wisconsin-Madison Graduate School

Faculty Advisor: Meyer Jackson,