GABA _B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

Abstract

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.presynaptic inhibition | mTLE model | patch clamp N euronal activity in the hippocampus shows oscillations in behavior-relevant frequency ranges including γ frequencies (30-80 Hz) (1). γ activity is prominent in the aroused brain and has been implicated in higher-level brain functions, such as sensory binding, perception (2), and storage and recall of information (3, 4). At the same time, γ frequency oscillations are also prevalent in epileptic patients and are most often observed at seizure onset during in depth EEG recordings (5). The GABAergic system plays a pivotal role in the generation of γ oscillations (6-8). However, it remains to be resolved how distinct GABAergic receptor subtypes, in particular GABA B receptors (GABA B Rs), contribute to the generation and modulation of pathological network oscillatory activity.GABA B Rs mediate slow inhibitory effects and control synaptic transmission and the excitability of neurons in cortical networks. GABA B Rs are expressed both postsynaptically in somatodendritic compartments and presynaptically in axon terminals, in excitatory principal cell and inhibitory interneurons (9-11). The effects of GABA B R activation on the network are dominated by inhibition leading to an overall dampened population activity. However, if GABAergic interneurons are effected dominantly, as observed for example, during high-frequency stimulation, GABA B R activation can produce disinhibition in principal cells (12,13). Accordingly, the role of GABA B Rs in epilepsy and seizure generation remains ambiguous. GABA B Rs ...

Functional Reduction in Cannabinoid-Sensitive Heterotypic Inhibition of Dentate Basket Cells in Epilepsy: Impact on Network Rhythms

“…In 4 of 4 post-SE AC-IN→FS-BC pairs, we found that SCH50911 reduced paired pulse ratio (i.e., increased paired pulse depression; IPSC2/IPSC1 in SCH50911 normalized to IPSC2/IPSC1 before SCH50911 perfusion: 70.3 ± 7.4%, P = 0.02, paired t-test, data not shown). Thus, our data are consistent with GABA B blockers increasing baseline synaptic release probability of the first IPSC and contributing to greater paired pulse depression of AC- IN→FS-BC synapses after SE and differ from the enhanced GABA B autoreceptors function observed in CA3 pyramidal cells after SE (Dugladze et al 2013).…”

“…Indeed, GABA B R are expressed in several classes of dentate interneurons including those expressing somatostatin, calretinin, and NPY (Sloviter et al 1999) and could undergo cell-type-specific changes in expression levels in these interneuronal populations following SE. Our demonstration of post-SE increase in GABA B -mediated suppression of FS-BC synaptic inhibition is consistent with recent findings in CA3 pyramidal cells in a mouse model of epilepsy (Dugladze et al 2013).…”

“…Together, these data demonstrate cell-type-specific steady-state GABA B R modulation of FS-BC synaptic inputs from AC-INs. In earlier studies examining pyramidal cell inhibition, blocking GABA B R was shown to reduce paired pulse depression (i.e., increase paired pulse ratio defined as the ratio of amplitude of IPSC2 to IPSC1) after SE (Dugladze et al 2013). On this basis, it was suggested that GABA B autoreceptors contribute significantly to paired pulse depression of IPSCs in CA3 pyramidal cells.…”

“…Previous studies have demonstrated cell-type-specific expression of GABA B receptors (GABA B R) in neurons expressing various neurochemical markers including CCK, and a selective lack of GABA B R in PV-expressing interneurons (Sloviter et al 1999). Recent studies have identified an increase in GABA B R function in the hippocampus in an experimental model of epilepsy in mice (Dugladze et al 2013). Since activation of presynaptic GABA B autoreceptors can reduce synaptic release, we examined whether an increase in GABA B R function contributes to the post-SE decrease in reliability of AC-IN→FS-BC synapses.…”

“…We find that SE undermines FS-BC inputs from adapting interneurons, which contribute to theta modulation of gamma oscillations in network simulations (White et al 2000;Rotstein et al 2005). While earlier studies manipulated steady-state current to model reduction in inhibitory drive (Dugladze et al 2013), we implemented mechanistically based simulations in which release probability was manipulated to model the reduction in frequency of AC-IN inputs to FS-BCs. Reducing reliability of heterotypic inputs to FS-BCs consistently reduced network theta oscillations and could contribute to reduction in entorhinal-dentate theta coupling observed in experimental epilepsy (Froriep et al 2012).…”