Rationale: GABAergic transmission can mediate inhibition, synchronization or in some cases excitation and is an important regulator of oscillatory activity and seizure generation. However, the precise roles and interactions between GABAergic transmission, oscillations and seizures remain a topic of debate. We tested the hypothesis that reducing GABAergic transmission when excitatory transmission is enhanced will reduce synchrony and seizure incidence.
Methods: Extracellular field potentials were recorded for 2 hr using a multi-electrode array of 60 electrodes in acute entorhino-hippocampal slices isolated from control or pilocarpine-treated epileptic rats. Network activity was induced with 1) 0mM Mg
2+ buffer to enhance excitatory transmission; 2) application of the GABA
A receptor antagonist bicuculline (10μM, BMI) and elevated K
+ (7.5mM) to block GABAergic transmission and increase excitability or 3) 0mM Mg
2+ buffer containing BMI to increase excitatory and block inhibitory transmission concurrently. Activity was mapped to distinct regions. Interictal spikes (<80ms), epileptiform events (80ms-3s) and electrographic seizures (
> 3s) were quantified from raw field potentials. Slow oscillations (1-100Hz), ripples (101-200Hz) and fast ripples (201-1000Hz) were isolated by band pass filtering. Autocorrelations within hippocampal regions and covariance across regions were used to measure synchrony.
Results: In general, for interictal spikes and epileptiform events, the highest incidence and biggest differences between control and epileptic tissue was seen when excitatory transmission was increased and GABAergic transmission was blocked. In contrast, for electrographic seizures, the highest incidence and biggest differences between control and epileptic tissue was observed when excitatory transmission was enhanced and GABAergic transmission was intact.
Under conditions that increased interictal spikes and epileptiform events in epileptic vs control (excitatory transmission enhanced, GABAergic transmission blocked), both the number and synchrony of slow oscillations was high. However, while the number of high frequency oscillations also was increased, their synchrony was reduced. The number of spectral peaks for all oscillation frequencies was increased under these conditions. Conversely, under conditions that yielded the highest incidence of seizures (excitatory transmission enhanced, GABAergic transmission intact), the number of high frequency oscillations was not dramatically different, but their synchrony was increased in epileptic vs control. Conclusions: Intact GABAergic transmission appeared to be important for seizure generation and synchronizing fast oscillations when excitatory transmission was increased. Synchrony of low frequency oscillations was greatest when GABAergic transmission was blocked, suggesting opposing roles of GABAergic transmission in mediating synchronization of activity. Supported by CDMRP grant PR030035 (SB) and EFA Postdoctoral Fellowship (BG)