Pathophysiological role of extrasynaptic GABAA receptors in typical absence epilepsy

GABA is the principal inhibitory neurotransmitter in the mammalian CNS. It acts via two classes of receptors, the GABAA, a ligand gated ion channel (ionotropic receptor) and the metabotropic G-protein coupled GABAB receptor. While synaptic GABAA receptors underlie classical ‘phasic’ GABAA receptor-mediated inhibition, extrasynaptic GABAA receptors (eGABAAR) mediate a new form of inhibition, termed ‘tonic’ GABAA inhibition. The subunit composition of eGABAARs differs from those present at the synapse, resulting in pharmacologically and functionally distinct properties. In this mini-review the findings presented at the 2nd Neuroscience Day meeting held last July in Malta will be summarised. Particular emphasis will be given to the important pathophysiological role of eGABAAR within thalamocortical circuits as a major player in nonconvulsive absence epilepsy. The new findings presented at the conference suggest that enhanced tonic inhibition is a common cause of seizures in several animal models of absence epilepsy and may provide new targets for therapeutic intervention.peer-reviewe

Monoamine modulation of tonic GABAA inhibition

In recent years, it has become evident that many neurotransmitters and endogenous ligands differentially modulate synaptic γ-aminobutyric acid type A receptors (sGABAARs) and extrasynaptic GABAAR (eGABAARs). In this mini-review, we will summarize the available evidence on the ability of the monoamines serotonin (5-HT), noradrenaline (NA), and, in particular, dopamine (DA) to alter the functional response of eGABAARs, thus either increasing or decreasing tonic GABAA inhibition. Although this field of research is still in its infancy, it has already been demonstrated that eGABAARs show a nucleus-selective and neuronal-type-selective regulation by monoamines in a way that differs from that of sGABAARs. Further work will undoubtedly advance our knowledge of the intricate talk between monoamines and eGABAAR and may ultimately provide new leads for the treatment of neurological and neuropsychiatric disorders, where alteration in GABAAR function is one of the underlying causes.peer-reviewe

Differential control by 5-HT and 5-HT1A, 2A, 2C receptors of phasic and tonic GABAA inhibition in the visual thalamus

Thalamocortical (TC) neurons, including those of the dorsal lateral geniculate nucleus (dLGN), one of the visual sensory thalamic nuclei, exhibit two forms of GABAA receptor-mediated inhibition: phasic or classical inhibitory postsynaptic currents (IPSCs) generated by the activation of synaptic GABAA receptors (sGABAAR) and tonic inhibition generated by extra- or peri-synaptic GABAA receptors (eGABAAR). The source of GABA mediating tonic inhibition mostly arises from spillover out of the synaptic cleft, because tonic inhibition is blocked by TTX and removal of extracellular Ca2+ in adult murine dLGN TC neurons. Therefore, modulation of vesicular GABA release may not only affect phasic but also tonic inhibition. Previous work in the cat and rat dLGN has shown that several neurotransmitters, including acetylcholine, serotonin (5-HT), dopamine, and norepinephrine can modulate vesicular GABA release from inhibitory interneurons, resulting in changes in phasic inhibition (IPSC frequency), primarily through presynaptic modulation of GABA release from dendro-dendritic synapses [5]. However, except for dopamine in the somatosensory thalamus, the effect of these neurotransmitters on tonic GABAA inhibition in TC neurons has not been examined. Here, we investigated whether 5-HT and its 5-HT1A, 5-HT2A and 5-HT2C receptors exert a control over tonic and phasic GABAA currents in dLGN TC neurons. We used whole cell patch clamp recordings in coronal slices (300 mm) containing the dLGN from postnatal day 20–25 Wistar rats. Data analysis and experimental procedures were similar to those previously described and in accordance with the Animals (Scientific Procedures) Act 1986 (UK). Focal application of gabazine (GBZ, 100 mM) was used to reveal the presence of tonic GABAA current (Figure 1). All serotonergic drugs were dissolved in the recording solution, and their concentrations, co-administration, and effects on phasic and tonic GABAA current are shown in Table 1 and Figure 1. We found that 5-HT enhances phasic GABAA inhibition (i.e., spontaneous IPSCs), but has no action on tonic inhibition. These effects are identical to those observed following 5-HT1A/7R activation with 8-OH-DPAT. On the other hand, α-M-5-HT and mCPP enhances and reduces, respectively, both phasic and tonic GABAA inhibition. These effects are dependent on 5-HT2AR and 5-HT2CR activation, respectively, as they are blocked by co-perfusion with selective antagonists, ketanserin, and SB242084. Thus, the lack of 5-HT modulation of tonic inhibition might be explained by the counterbalance of co-activation of 5-HT2ARs and 5-HT2CRs by the endogenous ligand.peer-reviewe

Sodium current in rat and cat thalamocortical neurons:role of a non-inactivating component in tonic and burst firing

The properties of the Na+ current present in thalamocortical neurons of the dorsal lateral geniculate nucleus were investigated in dissociated neonate rat and cat neurons and in neurons from slices of neonate and adult rats using patch and sharp electrode recordings. The steady-state activation and inactivation of the transient Na+ current (INa) was well fitted with a Boltzmann curve (voltage of half-maximal activation and inactivation, V1/2, -29.84 mV and -70.04 mV, respectively). Steady-state activation and inactivation curves showed a small region of overlap, indicating the occurrence of a / Na window current.  / Na decay could be fitted with a single exponential function, consistent with the presence of only one channel type. Voltage ramp and step protocols showed the presence of a noninactivating component of the Na+ current (/ NaP) that activated at potentials more negative (V1/2 = -56.93 mV) than those of INa. The maximal amplitude of / NaP was approximately 2.5% of INa, thus significantly greater than the calculated contribution (0.2%) of the I Na window component. Comparison of results from dissociated neurons and neurons in slices suggested a dendritic as well as a somatic localization of I NaP. Inclusion of papain in the patch electrode removed the fast inactivation of / Na and induced a current with voltage-dependence (V1/2 = -56.92) and activation parameters similar to those of I NaP. Current-clamp recordings with sharp electrodes showed that I NaP contributed to depolarizations evoked from potentials of approximately -60 mV and unexpectedly to the amplitude and latency of low-threshold Ca2+ potentials, suggesting that this noninactivating component of the Na+ channel population plays an important role in the integrative properties of thalamocortical neurons during both tonic and burst-firing patterns

Sleep waves in a large‐scale corticothalamic model constrained by activities intrinsic to neocortical networks and single thalamic neurons

Aim: Many biophysical and non‐biophysical models have been able to reproduce the corticothalamic activities underlying different EEG sleep rhythms but none of them included the known ability of neocortical networks and single thalamic neurons to generate some of these waves intrinsically. Methods: We built a large‐scale corticothalamic model with a high fidelity in anatomical connectivity consisting of a single cortical column and first‐ and higher‐order thalamic nuclei. The model is constrained by different neocortical excitatory and inhibitory neuronal populations eliciting slow (<1 Hz) oscillations and by thalamic neurons generating sleep waves when isolated from the neocortex. Results: Our model faithfully reproduces all EEG sleep waves and the transition from a desynchronized EEG to spindles, slow (<1 Hz) oscillations, and delta waves by progressively increasing neuronal membrane hyperpolarization as it occurs in the intact brain. Moreover, our model shows that slow (<1 Hz) waves most often start in a small assembly of thalamocortical neurons though they can also originate in cortical layer 5. Moreover, the input of thalamocortical neurons increases the frequency of EEG slow (<1 Hz) waves compared to those generated by isolated cortical networks. Conclusion: Our simulations challenge current mechanistic understanding of the temporal dynamics of sleep wave generation and suggest testable predictions

Variable action potential backpropagation during tonic firing and low-threshold spike bursts in thalamocortical but not thalamic reticular nucleus neurons

Backpropagating action potentials (bAPs) are indispensable in dendritic signaling. Conflicting Ca2-imaging data and an absence of dendritic recording data means that the extent of backpropagation in thalamocortical (TC) and thalamic reticular nucleus (TRN) neurons remains unknown. Because TRN neurons signal electrically through dendrodendritic gap junctions and possibly via chemical dendritic GABAergic synapses, as well as classical axonal GABA release, this lack of knowledge is problematic. To address this issue, we made two-photon targeted patch-clamp recordings from rat TC and TRN neuron dendrites to measure bAPs directly. These recordings reveal that “tonic”’ and low-threshold-spike (LTS) “burst” APs in both cell types are always recorded first at the soma before backpropagating into the dendrites while undergoing substantial distance-dependent dendritic amplitude attenuation. In TC neurons, bAP attenuation strength varies according to firing mode. During LTS bursts, somatic AP half-width increases progressively with increasing spike number, allowing late-burst spikes to propagate more efficiently into the dendritic tree compared with spikes occurring at burst onset. Tonic spikes have similar somatic half-widths to late burst spikes and undergo similar dendritic attenuation. In contrast, in TRN neurons, AP properties are unchanged between LTS bursts and tonic firing and, as a result, distance-dependent dendritic attenuation remains consistent across different firing modes. Therefore, unlike LTS-associated global electrical and calcium signals, the spatial influence of bAP signaling in TC and TRN neurons is more restricted, with potentially important behavioral-state-dependent consequences for synaptic integration and plasticity in thalamic neurons

The Thalamus as a Low Pass Filter. Filtering at the Cellular Level does Not Equate with Filtering at the Network Level

In the mammalian central nervous system, most sensory information passes through primary sensory thalamic nuclei, however the consequence of this remains unclear. Various propositions exist, likening the thalamus to a gate, or a high pass filter. Here, using a simple leaky integrate and fire model based on physiological parameters, we show that the thalamus behaves akin to a low pass filter. Specifically, as individual cells in the thalamus rely on consistent drive to spike, stimuli that is rapidly and continuously changing over time such that it activates sensory cells with different receptive fields are unable to drive thalamic spiking. This means that thalamic encoding is robust to sensory noise, however it induces a lag in sensory representation. Thus, the thalamus stabilizes encoding of sensory information, at the cost of response rate

Spike-and-wave discharges of absence seizures in a sleep waves-constrained corticothalamic model

Aims Recurrent network activity in corticothalamic circuits generates physiological and pathological EEG waves. Many computer models have simulated spike-and-wave discharges (SWDs), the EEG hallmark of absence seizures (ASs). However, these models either provided detailed simulated activity only in a selected territory (i.e., cortical or thalamic) or did not test whether their corticothalamic networks could reproduce the physiological activities that are generated by these circuits. Methods Using a biophysical large-scale corticothalamic model that reproduces the full extent of EEG sleep waves, including sleep spindles, delta, and slow (<1 Hz) waves, here we investigated how single abnormalities in voltage- or transmitter-gated channels in the neocortex or thalamus led to SWDs. Results We found that a selective increase in the tonic γ-aminobutyric acid type A receptor (GABA-A) inhibition of first-order thalamocortical (TC) neurons or a selective decrease in cortical phasic GABA-A inhibition is sufficient to generate ~4 Hz SWDs (as in humans) that invariably start in neocortical territories. Decreasing the leak conductance of higher-order TC neurons leads to ~7 Hz SWDs (as in rodent models) while maintaining sleep spindles at 7–14 Hz. Conclusion By challenging key features of current mechanistic views, this simulated ictal corticothalamic activity provides novel understanding of ASs and makes key testable predictions

Developmental changes of GABA immunoreactivity in cortico-thalamic networks of an absence seizure model

Absence seizures (ASs) are associated with abnormalities in gamma-aminobutyric acid (GABA) neurotransmission in the thalamus and the cortex. In the present study, we used light microscopy GABA immunocytochemistry to quantify the GABA-immunoreactive (GABA-IR) neurons and neuropil in the thalamic ventral basal (VB) nucleus, the nucleus reticularis thalami (NRT), the dorsal lateral geniculate (dLGN), the primary motor cortex (M1) and perioral region of the somatosensory cortex (S1po) of genetic absence epilepsy rats from Strasbourg (GAERS). We used both the relative non-epileptic control (NEC) and normal Wistar rats as control strains, and investigated GABA immunostaining at postnatal day 15 (P15), P25, and P90. The main findings were i) an increase in GABA-IR neuropil in the VB at P25 and P90 in GAERS but not in NEC and Wistar rats; ii) an increase in NRT GABA-IR neurons in GAERS and NEC, but not Wistar, rats at both P25 and P90; and iii) an increase in GABA-IR neuron density in S1po of GAERS at P25 and P90 and in Wistar at P90. These results indicate that the increased GABAergic innervation in the VB at P25 most likely contributes to the enhanced tonic inhibition observed in GAERS prior to AS onset, whereas the lack of any anatomo-morphological GABAergic differences in GAERS S1po suggests that functional more than structural abnormalities underlie the origin of cortical paroxysms in S1po of this AS model

The thalamus as a low pass filter: filtering at the cellular level does not equate with filtering at the network level

In the mammalian central nervous system, most sensory information passes through primary sensory thalamic nuclei, however the consequence of this remains unclear. Various propositions exist, likening the thalamus to a gate, or a high pass filter. Here, using a simple leaky integrate and fire model based on physiological parameters, we show that the thalamus behaves akin to a low pass filter. Specifically, as individual cells in the thalamus rely on consistent drive to spike, stimuli that is rapidly and continuously changing over time such that it activates sensory cells with different receptive fields are unable to drive thalamic spiking. This means that thalamic encoding is robust to sensory noise, however it induces a lag in sensory representation. Thus, the thalamus stabilizes encoding of sensory information, at the cost of response rate