Highlights • Ionic plasticity of GABA signaling relies on short-term and long term changes in EGABA. • Cl− transport and carboanhydrases play a key role in ionic plasticity and epilepsy. • GABAergic ...transmission has both seizure-suppressing and seizure-promoting effects. • TrkB and calpain act on GABA signaling to coordinate the process of epileptogenesis. • GABA signaling has context-specific and age-specific effects in health and disease.
Electrical activity in neurons requires a seamless functional coupling between plasmalemmal ion channels and ion transporters. Although ion channels have been studied intensively for several decades, ...research on ion transporters is in its infancy. In recent years, it has become evident that one family of ion transporters, cation-chloride cotransporters (CCCs), and in particular K(+)-Cl(-) cotransporter 2 (KCC2), have seminal roles in shaping GABAergic signalling and neuronal connectivity. Studying the functions of these transporters may lead to major paradigm shifts in our understanding of the mechanisms underlying brain development and plasticity in health and disease.
Our ability to perceive weak signals is correlated among consecutive trials and fluctuates slowly over time. Although this "streaking effect" has been known for decades, the underlying neural network ...phenomena have remained largely unidentified. We examined the dynamics of human behavioral performance and its correlation with infraslow (0.01-0.1 Hz) fluctuations in ongoing brain activity. Full-band electroencephalography revealed prominent infraslow fluctuations during the execution of a somatosensory detection task. Similar fluctuations were predominant also in the dynamics of behavioral performance. The subjects' ability to detect the sensory stimuli was strongly correlated with the phase, but not with the amplitude of the infraslow EEG fluctuations. These data thus reveal a direct electrophysiological correlate for the slow fluctuations in human psychophysical performance. We then examined the correlation between the phase of infraslow EEG fluctuations and the amplitude of 1-40 Hz neuronal oscillations in six frequency bands. Like the behavioral performance, the amplitudes in these frequency bands were robustly correlated with the phase of the infraslow fluctuations. These data hence suggest that the infraslow fluctuations reflect the excitability dynamics of cortical networks. We conclude that ongoing 0.01-0.1 Hz EEG fluctuations are prominent and functionally significant during execution of cognitive tasks.
GABAergic excitatory K+o transients can be readily evoked in the mature rat hippocampus by intense activation of GABAA receptors (GABAARs). Here we show that these K+o responses induced by ...high‐frequency stimulation or GABAA agonist application are generated by the neuronal K+–Cl− cotransporter KCC2 and that the transporter‐mediated KCl extrusion is critically dependent on the bicarbonate‐driven accumulation of Cl− in pyramidal neurons. The mechanism underlying GABAergic K+o transients was studied in CA1 stratum pyramidale using intracellular sharp microelectrodes and extracellular ion‐sensitive microelectrodes. The evoked K+o transients, as well as the associated afterdischarges, were strongly suppressed by 0.5–1 mm furosemide, a KCl cotransport inhibitor. Importantly, the GABAAR‐mediated intrapyramidal accumulation of Cl−, as measured by monitoring the reversal potential of fused IPSPs, was unaffected by the drug. It was further confirmed that the reduction in the K+o transients was not due to effects of furosemide on the Na+‐dependent K+‐Cl− cotransporter NKCC1 or on intraneuronal carbonic anhydrase activity. Blocking potassium channels by Ba2+ enhanced K+o transients whereas pyramidal cell depolarizations were attenuated in further agreement with a lack of contribution by channel‐mediated K+ efflux. The key role of the GABAAR channel‐mediated anion fluxes in the generation of the K+o transients was examined in experiments where bicarbonate was replaced with formate. This anion substitution had no significant effect on the rate of Cl− accumulation, K+o response or afterdischarges. Our findings reveal a novel excitatory mode of action of KCC2 that can have substantial implications for the role of GABAergic transmission during ictal epileptiform activity.
Neurons maintain a low concentration of the negatively charged ion, chloride. When the main inhibitory neurotransmitter, GABA, binds to its receptor, an ion channel opens permitting a rapid influx of chloride and the membrane potential shifts in the negative direction. The principal neuronal chloride extruder is KCC2, a member of the potassium–chloride cotransporter family. As KCC2‐mediated chloride extrusion is driven by the high intracellular potassium concentration, the activity of KCC2 both lowers the internal chloride concentration and increases the extracellular potassium concentration. Following intense GABA transmission, this increase in potassium can reach such a high level that it, paradoxically, leads to excitation of neurons. This novel finding may shed light on the mechanisms underlying seizures.
Network activity in the brain is associated with a transient increase in extracellular K+ concentration. The excess K+ is removed from the extracellular space by mechanisms proposed to involve ...Kir4.1‐mediated spatial buffering, the Na+/K+/2Cl− cotransporter 1 (NKCC1), and/or Na+/K+‐ATPase activity. Their individual contribution to K+o management has been of extended controversy. This study aimed, by several complementary approaches, to delineate the transport characteristics of Kir4.1, NKCC1, and Na+/K+‐ATPase and to resolve their involvement in clearance of extracellular K+ transients. Primary cultures of rat astrocytes displayed robust NKCC1 activity with K+o increases above basal levels. Increased K+o produced NKCC1‐mediated swelling of cultured astrocytes and NKCC1 could thereby potentially act as a mechanism of K+ clearance while concomitantly mediate the associated shrinkage of the extracellular space. In rat hippocampal slices, inhibition of NKCC1 failed to affect the rate of K+ removal from the extracellular space while Kir4.1 enacted its spatial buffering only during a local K+o increase. In contrast, inhibition of the different isoforms of Na+/K+‐ATPase reduced post‐stimulus clearance of K+ transients. The astrocyte‐characteristic α2β2 subunit composition of Na+/K+‐ATPase, when expressed in Xenopus oocytes, displayed a K+ affinity and voltage‐sensitivity that would render this subunit composition specifically geared for controlling K+o during neuronal activity. In rat hippocampal slices, simultaneous measurements of the extracellular space volume revealed that neither Kir4.1, NKCC1, nor Na+/K+‐ATPase accounted for the stimulus‐induced shrinkage of the extracellular space. Thus, NKCC1 plays no role in activity‐induced extracellular K+ recovery in native hippocampal tissue while Kir4.1 and Na+/K+‐ATPase serve temporally distinct roles. GLIA 2014;62:608–622
Main Points
Kir4.1 and Na+/K+−ATPase serve distinct roles in recovery of activity‐induced K+o in hippocampus.
The α2β2 Na+/K+−ATPase is specifically geared for controlling K+o.
NKCC1 is not involved in stimulus‐induced shrinkage of the extracellular space.
GABAergic terminals of axo-axonic cells (AACs) are exclusively located on the axon initial segment (AIS) of cortical principal neurons, and they are generally thought to exert a powerful inhibitory ...action. However, recent work (Szabadics et al., 2006) indicates that this input from AACs can be depolarizing and even excitatory. Here, we used local photolysis of caged GABA to measure reversal potentials (E(GABA)) of GABA(A) receptor-mediated currents and to estimate the local chloride concentration in the AIS compared with other cellular compartments in dentate granule cells and neocortical pyramidal neurons. We found a robust axo-somato-dendritic gradient in which the E(GABA) values from the AIS to the soma and dendrites become progressively more negative. Data from NKCC1(-/-) and bumetanide-exposed neurons indicated that the depolarizing E(GABA) at the AIS is set by chloride uptake mediated by the Na-K-2Cl cotransporter NKCC1. Our findings demonstrate that spatially distinct interneuronal inputs can induce postsynaptic voltage responses with different amplitudes and polarities as governed by the subcellular distributions of plasmalemmal chloride transporters.
Objective
Seizures are common in neonates recovering from birth asphyxia but there is general consensus that current pharmacotherapy is suboptimal and that novel antiseizure drugs are needed. We ...recently showed in a rat model of birth asphyxia that seizures are triggered by the post‐asphyxia recovery of brain pH. Here our aim was to investigate whether carbonic anhydrase inhibitors (CAIs), which induce systemic acidosis, block the post‐asphyxia seizures.
Methods
The CAIs acetazolamide (AZA), benzolamide (BZA), and ethoxzolamide (EZA) were administered intraperitoneally or intravenously to 11‐day‐old rats exposed to intermittent asphyxia (30 min; three 7+3 min cycles of 9% and 5% O2 at 20% CO2). Electrode measurements of intracortical pH, Po2, and local field potentials (LFPs) were made under urethane anesthesia. Convulsive seizures and blood acid‐base parameters were examined in freely behaving animals.
Results
The three CAIs decreased brain pH by 0.14–0.17 pH units and suppressed electrographic post‐asphyxia seizures. AZA, BZA, and EZA differ greatly in their lipid solubility (EZA > AZA > BZA) and pharmacokinetics. However, there were only minor differences in the delay (range 0.8–3.7 min) from intraperitoneal application to their action on brain pH. The CAIs induced a modest post‐asphyxia elevation of brain Po2 that had no effect on LFP activity. AZA was tested in freely behaving rats, in which it induced a respiratory acidosis and decreased the incidence of convulsive seizures from 9 of 20 to 2 of 17 animals.
Significance
AZA, BZA, and EZA effectively block post‐asphyxia seizures. Despite the differences in their pharmacokinetics, they had similar effects on brain pH, which indicates that their antiseizure mode of action was based on respiratory (hypercapnic) acidosis resulting from inhibition of blood‐borne and extracellular vascular carbonic anhydrases. AZA has been used for several indications in neonates, suggesting that it can be safely repurposed for the treatment of neonatal seizures as an add‐on to the current treatment regimen.
During birth in mammals, a pronounced surge of fetal peripheral stress hormones takes place to promote survival in the transition to the extrauterine environment. However, it is not known whether the ...hormonal signaling involves central pathways with direct protective effects on the perinatal brain. Here, we show that arginine vasopressin specifically activates interneurons to suppress spontaneous network events in the perinatal hippocampus. Experiments done on the altricial rat and precocial guinea pig neonate demonstrated that the effect of vasopressin is not dependent on the level of maturation (depolarizing vs. hyperpolarizing) of postsynaptic GABAA receptor actions. Thus, the fetal mammalian brain is equipped with an evolutionarily conserved mechanism well-suited to suppress energetically expensive correlated network events under conditions of reduced oxygen supply at birth.
Neuroinflammation is a salient part of diverse neurological and psychiatric pathologies that associate with neuronal hyperexcitability, but the underlying molecular and cellular mechanisms remain to ...be identified. Here, we show that peripheral injection of lipopolysaccharide (LPS) renders the dentate gyrus (DG) hyperexcitable to perforant pathway stimulation in vivo and increases the internal spiking propensity of dentate granule cells (DGCs) in vitro 24 h post-injection (hpi). In parallel, LPS leads to a prominent downregulation of chloride extrusion via KCC2 and to the emergence of NKCC1-mediated chloride uptake in DGCs under experimental conditions optimized to detect specific changes in transporter efficacy. These data show that acute neuroinflammation leads to disruption of neuronal chloride regulation, which unequivocally results in a loss of GABAergic inhibition in the DGCs, collapsing the gating function of the DG. The present work provides a mechanistic explanation for neuroinflammation-driven hyperexcitability and consequent cognitive disturbance.
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•Peripheral LPS renders the adult DG hyperexcitable to perforant pathway stimulation•Excitation-spike coupling in DG is enhanced, pointing to an erosion of inhibition•LPS-induced inflammation suppresses KCC2-driven Cl− extrusion and boosts Cl− uptake by NKCC1•Functional downregulation of KCC2 is associated with downregulation of KCC2 mRNA expression
Kurki et al. show that acute neuroinflammation induced by peripheral LPS injection renders the dentate gyrus hyperexcitable, which is attributable to a prominent downregulation of chloride extrusion via KCC2 and the emergence of NKCC1-mediated chloride uptake in dentate granule cells, leading to a loss of GABAergic inhibition.
Chemotherapy aided by opening of the blood-brain barrier with intra-arterial infusion of hyperosmolar mannitol improves the outcome in primary central nervous system lymphoma. Proper opening of the ...blood-brain barrier is crucial for the treatment, yet there are no means available for its real-time monitoring. The intact blood-brain barrier maintains a mV-level electrical potential difference between blood and brain tissue, giving rise to a measurable electrical signal at the scalp. Therefore, we used direct-current electroencephalography (DC-EEG) to characterize the spatiotemporal behavior of scalp-recorded slow electrical signals during blood-brain barrier opening. Nine anesthetized patients receiving chemotherapy were monitored continuously during 47 blood-brain barrier openings induced by carotid or vertebral artery mannitol infusion. Left or right carotid artery mannitol infusion generated a strongly lateralized DC-EEG response that began with a 2 min negative shift of up to 2000 μV followed by a positive shift lasting up to 20 min above the infused carotid artery territory, whereas contralateral responses were of opposite polarity. Vertebral artery mannitol infusion gave rise to a minimally lateralized and more uniformly distributed slow negative response with a posterior-frontal gradient. Simultaneously performed near-infrared spectroscopy detected a multiphasic response beginning with mannitol-bolus induced dilution of blood and ending in a prolonged increase in the oxy/deoxyhemoglobin ratio. The pronounced DC-EEG shifts are readily accounted for by opening and sealing of the blood-brain barrier. These data show that DC-EEG is a promising real-time monitoring tool for blood-brain barrier disruption augmented drug delivery.
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