Cell-Type Specific Inhibition Controls the High-Frequency Oscillations in the Medial Entorhinal Cortex.

The medial entorhinal cortex (mEC) plays a critical role for spatial navigation and memory. While many studies have investigated the principal neurons within the entorhinal cortex, much less is known about the inhibitory circuitries within this structure. Here, we describe for the first time in the mEC a subset of parvalbumin-positive (PV+) interneurons (INs)-stuttering cells (STUT)-with morphological, intrinsic electrophysiological, and synaptic properties distinct from fast-spiking PV+ INs. In contrast to the fast-spiking PV+ INs, the axon of the STUT INs also terminated in layer 3 and showed subthreshold membrane oscillations at gamma frequencies. Whereas the synaptic output of the STUT INs was only weakly reduced by a µ-opioid agonist, their inhibitory inputs were strongly suppressed. Given these properties, STUT are ideally suited to entrain gamma activity in the pyramidal cell population of the mEC. We propose that activation of the µ-opioid receptors decreases the GABA release from the PV+ INs onto the STUT, resulting in disinhibition of the STUT cell population and the consequent increase in network gamma power. We therefore suggest that the opioid system plays a critical role, mediated by STUT INs, in the neural signaling and oscillatory network activity within the mEC.

GABA(B) autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice.

GABA(B) receptors (GABA(B)Rs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA(B)R agonist baclofen can also promote excitability and seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 µM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 µM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK(+) BCs), through enhanced inhibition of GABA release via presynaptic GABA(B)Rs. We conclude that cell type-specific up-regulation of GABA(B)R-mediated autoinhibition in CCK(+) BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.