Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy

Selected mutations in the human alpha4 or beta2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4(S252F) and Chrna4(+L264)) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II/III cortical pyramidal cells reveal a >20-fold increase in nicotine-evoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of picrotoxin, a use-dependent gamma-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant alpha4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons.     

A hippocampal interneuron associated with the mossy fiber system

Network properties of the hippocampus emerge from the interaction of principal cells and a heterogeneous population of interneurons expressing gamma-aminobutyric acid (GABA). To understand these interactions, the synaptic connections of different types of interneurons need to be elucidated. Here we describe a type of inhibitory interneuron of the hippocampal CA3 region that has an axon coaligned with the mossy fibers. Whole-cell patch-clamp recordings, in combination with intracellular biocytin filling, were made from nonpyramidal cells of the stratum lucidum under visual control. Mossy fiber-associated (MFA) interneurons generated brief action potentials followed by a prominent after-hyperpolarization. Subsequent visualization revealed an extensive axonal arbor which was preferentially located in the stratum lucidum of CA3 and often invaded the hilus. The dendrites of MFA interneurons were mainly located in the strata radiatum and oriens, suggesting that these cells are primarily activated by associational and commissural fibers. Electron microscopic analysis showed that axon terminals of MFA interneurons established symmetric synaptic contacts predominantly on proximal apical dendritic shafts, and to a lesser degree, on somata of pyramidal cells. Synaptic contacts were also found on GABAergic interneurons of the CA3 region and putative mossy cells of the hilus. Inhibitory postsynaptic currents (IPSCs) elicited by MFA interneurons in simultaneously recorded pyramidal cells had fast kinetics (half duration, 3.6 ms) and were blocked by the GABA(A) receptor antagonist bicuculline. Thus, MFA interneurons are GABAergic cells in a position to selectively suppress the mossy fiber input, an important requirement for the recall of memory traces from the CA3 network.     

Synaptic disinhibition during maintenance of long-term potentiation in the CA1 hippocampal subfield.

Long-term potentiation (LTP) in the CA1 region of the hippocampus is widely believed to occur through a strengthening of efficacy of excitatory synapses between afferent fibers and pyramidal cells. An alternative mechanism of LTP, reduction of efficacy of synaptic inhibition, was examined in the present report. The present study demonstrates that the maintenance of LTP in the CA1 hippocampal subfield of guinea pigs is accompanied by impairment of type A gamma-aminobutyric acid (GABA) receptor function, particularly at apical dendritic sites of CA1 pyramidal cells. Enhanced excitability of GABAergic interneurons during LTP represents a strengthening of inhibitory efficacy. The net effect of opposite modifications of synaptic inhibition during LTP of CA1 pyramidal cells is an overall impairment of the strength of GABAergic inhibition, and disinhibition could contribute importantly to CA1 pyramidal cell LTP.     

A nonsynaptic mechanism underlying interictal discharges in human epileptic neocortex

Very fast oscillations (VFOs, >80 Hz) are important for physiological brain processes and, in excess, with certain epilepsies. Putative mechanisms for VFO include interneuron spiking and network activity in coupled pyramidal cell axons. It is not known whether either, or both, of these apply in pathophysiological conditions. Spontaneously occurring interictal discharges occur in human tissue in vitro, resected from neocortical epileptic foci. VFO associated with these discharges was manifest in both field potential and, with phase delay, in excitatory synaptic inputs to fast spiking interneurons. Recruitment of somatic pyramidal cell and interneuron spiking was low, with no correlation between VFO power and synaptic inputs to principal cells. Reducing synaptic inhibition failed to affect VFO occurrence, but they were abolished by reduced gap junction conductance. These data suggest a lack of a causal role for interneurons, and favor a nonsynaptic pyramidal cell network origin for VFO in epileptic human neocortex.     

Enhanced GABAergic inhibition preserves hippocampal structure and function in a model of epilepsy.

Extensive electrical stimulation of the perforant pathway input to the hippocampus results in a characteristic pattern of neuronal death, which is accompanied by an impairment of cognitive functions similar to that seen in human temporal lobe epilepsy. The excitotoxic hypothesis of epileptic cell death [Olney, J. W. (1978) in Kainic Acid as a Tool in Neurobiology, eds. McGeer, E., Olney, J. W. & McGeer, P. (Raven, New York), pp. 95-121; Olney, J. W. (1983) in Excitotoxins, eds. Fuxe, K., Roberts, P. J. & Schwartch, R. (Wenner-Gren International Symposium Series, Macmillan, London), Vol. 39, pp. 82-96; and Rothman, S. M. & Olney, J. W. (1986) Ann. Neurol. 19, 105-111] predicts an imbalance between excitation and inhibition, which occurs probably as a result of hyperactivity in afferent pathways or impaired inhibition. In the present study, we investigated whether the enhancement of gamma-aminobutyric acid (GABA)-mediated (GABAergic) inhibition of neurotransmission by blocking the GABA-metabolizing enzyme, GABA transaminase, could influence the histopathological and/or the behavioral outcome in this epilepsy model. We demonstrate that the loss of pyramidal cells and hilar somatostatin-containing neurons can be abolished by enhancing the level of synaptically released GABA, and that the preservation of hippocampal structure is accompanied by a significant sparing of spatial memory as compared with placebo-treated controls. These results suggest that enhanced GABAergic inhibition can effectively block the pathophysiological processes that lead to excitotoxic cell death and, as a result, protect the brain from seizure-induced cognitive impairment.     

Dysfunction of GABAA receptor glycolysis-dependent modulation in human partial epilepsy

A reduction in GABAergic neurotransmission has been put forward as a pathophysiological mechanism for human epilepsy. However, in slices of human epileptogenic neocortex, GABAergic inhibition can be clearly demonstrated. In this article we present data showing an increase in the functional lability of GABAergic inhibition in epileptogenic tissue compared with nonepileptogenic human tissue. We have previously shown that the glycolytic enzyme GAPDH is the kinase involved in the glycolysis-dependent endogenous phosphorylation of the alpha1-subunit of GABA(A) receptor, a mechanism necessary for maintaining GABA(A) function. In human epileptogenic cortex obtained during curative surgery of patients with partial seizures, we demonstrate an intrinsic deficiency of GABA(A) receptor endogenous phosphorylation resulting in an increased lability of GABAergic currents in neurons isolated from this tissue when compared with neurons from nonepileptogenic human tissue. This feature was not related to a reduction in the number of GABA(A) receptor alpha1-subunits in the epileptogenic tissue as measured by [(3)H]flunitrazepam photoaffinity labeling. Maintaining the receptor in a phosphorylated state either by favoring the endogenous phosphorylation or by inhibiting a membrane-associated phosphatase is needed to sustain GABA(A) receptor responses in epileptogenic cortex. The increased functional lability induced by the deficiency in phosphorylation can account for transient GABAergic disinhibition favoring seizure initiation and propagation. These findings imply new therapeutic approaches and suggest a functional link to the regional cerebral glucose hypometabolism observed in patients with partial epilepsy, because the dysfunctional GABAergic mechanism depends on the locally produced glycolytic ATP.     

Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons

Cortical information processing requires an orchestrated interaction between a large number of pyramidal cells and albeit fewer, but highly diverse GABAergic interneurons (INs). The diversity of INs is thought to reflect functional and structural specializations evolved to control distinct network operations. Consequently, specific cortical functions may be selectively modified by altering the input-output relationship of unique IN populations. Here, we report that persistently active cannabinoid receptors, the site of action of endocannabinoids, and the psychostimulants marijuana and hashish, switch off the output (mute) of a unique class of hippocampal INs. In paired recordings between cholecystokinin-immunopositive, mossy fiber-associated INs, and their target CA3 pyramidal cells, no postsynaptic currents could be evoked with single presynaptic action potentials or with repetitive stimulations at frequencies <25 Hz. Cannabinoid receptor antagonists converted these "mute" synapses into high-fidelity ones. The selective muting of specific GABAergic INs, achieved by persistent presynaptic cannabinoid receptor activation, provides a state-dependent switch in cortical networks.     

Two types of muscarinic response to acetylcholine in mammalian cortical neurons.

Applications of acetylcholine (AcCho) to pyramidal cells of guinea pig cingulate cortical slices maintained in vitro result in a short latency inhibition, followed by a prolonged increase in excitability. Cholinergic inhibition is mediated through the rapid excitation of interneurons that utilize the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This rapid excitation of interneurons is associated with a membrane depolarization and a decrease in neuronal input resistance. In contrast, AcCho-induced excitation of pyramidal cells is due to a direct action that produces a voltage-dependent increase in input resistance. In the experiments reported here, we investigated the possibility that these two responses are mediated by different subclasses of cholinergic receptors. The inhibitory and slow excitatory responses of pyramidal neurons were blocked by muscarinic but not by nicotinic antagonists. Pirenzepine was more effective in blocking the AcCho-induced slow depolarization than in blocking the hyperpolarization of pyramidal neurons. The two responses also varied in their sensitivity to various cholinergic agonists, making it possible to selectively activate either. These data suggest that AcCho may produce two physiologically and pharmacologically distinct muscarinic responses on neocortical neurons: slowly developing voltage-dependent depolarizations associated with an increase in input resistance in pyramidal cells and short-latency depolarizations associated with a decrease in input resistance in presumed GABAergic interneurons.     

Impaired hippocampal rhythmogenesis in a mouse model of mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (mTLE) is one of the most common forms of epilepsy, characterized by hippocampal sclerosis and memory deficits. Injection of kainic acid (KA) into the dorsal hippocampus of mice reproduces major electrophysiological and histopathological characteristics of mTLE. In extracellular recordings from the morphologically intact ventral hippocampus of KA-injected epileptic mice, we found that theta-frequency oscillations were abolished, whereas gamma oscillations persisted both in vivo and in vitro. Whole-cell recordings further showed that oriens-lacunosum-moleculare (O-LM) interneurons, key players in the generation of theta rhythm, displayed marked changes in their intrinsic and synaptic properties. Hyperpolarization-activated mixed cation currents (Ih) were significantly reduced, resulting in an increase in the input resistance and a hyperpolarizing shift in the resting membrane potential. Additionally, the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) was increased, indicating a stronger excitatory input to these neurons. As a consequence, O-LM interneurons increased their firing rate from theta to gamma frequencies during induced network activity in acute slices from KA-injected mice. Thus, our physiological data together with network simulations suggest that changes in excitatory input and synaptic integration in O-LM interneurons lead to impaired rhythmogenesis in the hippocampus that in turn may underlie memory deficit.     

Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons

Dendritic spines are of major importance in information processing and memory formation in central neurons. Estradiol has been shown to induce an increase of dendritic spine density on hippocampal neurons in vivo and in vitro. The neurotrophin brain-derived neurotrophic factor (BDNF) recently has been implicated in neuronal maturation, plasticity, and regulation of GABAergic interneurons. We now demonstrate that estradiol down-regulates BDNF in cultured hippocampal neurons to 40% of control values within 24 hr of exposure. This, in turn, decreases inhibition and increases excitatory tone in pyramidal neurons, leading to a 2-fold increase in dendritic spine density. Exogenous BDNF blocks the effects of estradiol on spine formation, and BDNF depletion with a selective antisense oligonucleotide mimics the effects of estradiol. Addition of BDNF antibodies also increases spine density, and diazepam, which facilitates GABAergic neurotransmission, blocks estradiol-induced spine formation. These observations demonstrate a functional link between estradiol, BDNF as a potent regulator of GABAergic interneurons, and activity-dependent formation of dendritic spines in hippocampal neurons.     

ErbB4 in parvalbumin-positive interneurons is critical for neuregulin 1 regulation of long-term potentiation

Neuregulin 1 (NRG1) is a trophic factor that acts by stimulating ErbB receptor tyrosine kinases and has been implicated in neural development and synaptic plasticity. In this study, we investigated mechanisms of its suppression of long-term potentiation (LTP) in the hippocampus. We found that NRG1 did not alter glutamatergic transmission at SC-CA1 synapses but increased the GABA(A) receptor-mediated synaptic currents in CA1 pyramidal cells via a presynaptic mechanism. Inhibition of GABA(A) receptors blocked the suppressing effect of NRG1 on LTP and prevented ecto-ErbB4 from enhancing LTP, implicating a role of GABAergic transmission. To test this hypothesis further, we generated parvalbumin (PV)-Cre;ErbB4(-/-) mice in which ErbB4, an NRG1 receptor in the brain, is ablated specifically in PV-positive interneurons. NRG1 was no longer able to increase inhibitory postsynaptic currents and to suppress LTP in PV-Cre;ErbB4(-/-) hippocampus. Accordingly, contextual fear conditioning, a hippocampus-dependent test, was impaired in PV-Cre;ErbB4(-/-) mice. In contrast, ablation of ErbB4 in pyramidal neurons had no effect on NRG1 regulation of hippocampal LTP or contextual fear conditioning. These results demonstrate a critical role of ErbB4 in PV-positive interneurons but not in pyramidal neurons in synaptic plasticity and support a working model that NRG1 suppresses LTP by enhancing GABA release. Considering that NRG1 and ErbB4 are susceptibility genes of schizophrenia, these observations contribute to a better understanding of how abnormal NRG1/ErbB4 signaling may be involved in the pathogenesis of schizophrenia.     

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

GABA_B receptors (GABA_BRs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA_BR 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_BRs. We conclude that cell type–specific up-regulation of GABA_BR-mediated autoinhibition in CCK⁺ BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.Neuronal 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_BRs), contribute to the generation and modulation of pathological network oscillatory activity.GABA_BRs mediate slow inhibitory effects and control synaptic transmission and the excitability of neurons in cortical networks. GABA_BRs are expressed both postsynaptically in somato-dendritic compartments and presynaptically in axon terminals, in excitatory principal cell and inhibitory interneurons (9–11). The effects of GABA_BR 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_BR activation can produce disinhibition in principal cells (12, 13). Accordingly, the role of GABA_BRs in epilepsy and seizure generation remains ambiguous. GABA_BRs are expected to have an overall antiepileptic effect, and indeed, the receptor KO animals show an epileptic phenotype (14). However, there is also evidence that the receptor agonist baclofen can induce seizures in patients after intrathecal application (15, 16). The picture is further complicated by the fact that GABA_BR expression can be altered in both epileptic patients, e.g., in mesial temporal lobe epilepsy (mTLE) (17), and animal models (18). Thus, cell type–specific alterations in GABA_BR expression may change network excitability during the progression of mTLE.Using a chronic kainate (KA) model of mTLE, which reproduces major electrophysiological and histopathological characteristics of human mTLE (19, 20), we studied the role of GABA_BRs in altered hippocampal network activity. Our results suggest that enhanced and persistent GABA_BR activation in epileptic mice suppresses the inhibitory output from hippocampal interneurons, in particular cholecystokinin (CCK)-expressing basket cells (BCs) onto pyramidal cells (PCs). This reduction in the inhibitory output of interneurons, in turn, leads to disinhibition in hippocampal networks, enhances γ activity, and promotes the transition to pathological hyperexcitability.     

Impaired long-term potentiation induction in dentate gyrus of calretinin-deficient mice

Calretinin (Cr) is a Ca²⁺ binding protein present in various populations of neurons distributed in the central and peripheral nervous systems. We have generated Cr-deficient (Cr^−/−) mice by gene targeting and have investigated the associated phenotype. Cr^−/− mice were viable, and a large number of morphological, biochemical, and behavioral parameters were found unaffected. In the normal mouse hippocampus, Cr is expressed in a widely distributed subset of GABAergic interneurons and in hilar mossy cells of the dentate gyrus. Because both types of cells are part of local pathways innervating dentate granule cells and/or pyramidal neurons, we have explored in Cr^−/− mice the synaptic transmission between the perforant pathway and granule cells and at the Schaffer commissural input to CA1 pyramidal neurons. Cr^−/− mice showed no alteration in basal synaptic transmission, but long-term potentiation (LTP) was impaired in the dentate gyrus. Normal LTP could be restored in the presence of the GABA_A receptor antagonist bicuculline, suggesting that in Cr^−/− dentate gyrus an excess of γ-aminobutyric acid (GABA) release interferes with LTP induction. Synaptic transmission and LTP were normal in CA1 area, which contains only few Cr-positive GABAergic interneurons. Cr^−/− mice performed normally in spatial memory task. These results suggest that expression of Cr contributes to the control of synaptic plasticity in mouse dentate gyrus by indirectly regulating the activity of GABAergic interneurons, and that Cr^−/− mice represent a useful tool to understand the role of dentate LTP in learning and memory.     

Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells

The axon initial segment (AIS) of pyramidal cells is a critical region for the generation of action potentials and for the control of pyramidal cell activity. Here we show that Na+ and K+ voltage-gated channels, together with other molecules involved in the localization of ion channels, are distributed asymmetrically in the AIS of pyramidal cells situated in the human temporal neocortex. There is a high density of Na+ channels distributed along the length of the AIS together with the associated proteins spectrin betaIV and ankyrin G. In contrast, Kv1.2 channels are associated with the adhesion molecule Caspr2, and they are mostly localized to the distal region of the AIS. In general, the distal region of the AIS is targeted by the GABAergic axon terminals of chandelier cells, whereas the proximal region is innervated, mostly by other types of GABAergic interneurons. We suggest that this molecular segregation and the consequent regional specialization of the GABAergic input to the AIS of pyramidal cells may have important functional implications for the control of pyramidal cell activity.     

Temporal-insular spreading time in temporal lobe epilepsy as a predictor of seizure outcome after temporal lobectomy

Insular involvement in temporal lobe epilepsy (TLE) has gradually been recognized since the widespread use of stereoelectroencephalography (SEEG). However, the correlation between insular involvement and failed temporal lobe surgery remains unclear. In this study, we analyzed the surgical outcomes of TLE patients who underwent temporal and insular SEEG recordings and explored the predictors of failed anterior temporal lobectomy (ATL) in these patients with temporal seizures.Forty-one patients who underwent ATL for drug-resistant TLE were examined using temporal and insular SEEG recordings. The clinical characteristics, SEEG data, and postoperative seizure outcomes of these patients were analyzed, and multivariate analysis was used to identify the predictors of surgical outcome.In this series, the ictal temporal discharges invaded the insula in 39 (95.1%) patients. Twenty-three (56.1%) patients were seizure-free (Engel class I) after ATL with at least 1 year follow-up. Only temporal-insular spreading time (TIST) was an independent predictor of postoperative seizure-free outcomes (P = .035). By creating receiver operating characteristic curves for TIST, 400 milliseconds was identified as the cutoff for classification. All patients were classified into 2 groups (TIST ≤ 400 milliseconds and TIST > 400 milliseconds) based on the cutoff value; the difference in seizure-free rates between the 2 groups was significant (P = .001).The very early insular involvement in TLE may be associated with poorer seizure outcomes after ATL. Our findings may be helpful for estimating the appropriate operative procedures and will be valuable for evaluating the prognosis of TLE patients with temporal-insular SEEG recordings and temporal lobectomy.     

Signaling between periglomerular cells reveals a bimodal role for GABA in modulating glomerular microcircuitry in the olfactory bulb

In the mouse olfactory bulb glomerulus, the GABAergic periglomerular (PG) cells provide a major inhibitory drive within the microcircuit. Here we examine GABAergic synapses between these interneurons. At these synapses, GABA is depolarizing and exerts a bimodal control on excitability. In quiescent cells, activation of GABA_A receptors can induce the cells to fire, thereby providing a means for amplification of GABA release in the glomerular microcircuit via GABA-induced GABA release. In contrast, GABA is inhibitory in neurons that are induced to fire tonically. PG–PG interactions are modulated by nicotinic acetylcholine receptors (nAChRs), and our data suggest that changes in intracellular calcium concentrations triggered by nAChR activation can be amplified by GABA release. Our results suggest that bidirectional control of inhibition in PG neurons can allow for modulatory inputs, like the cholinergic inputs from the basal forebrain, to determine threshold set points for filtering out weak olfactory inputs in the glomerular layer of the olfactory bulb via the activation of nAChRs.The balance of excitation and inhibition is critical for the normal functioning of brain networks. Timed inhibition of principal neurons modulates circuit output and contributes to network synchrony and oscillation. GABAergic interneurons play a key role in regulating these network properties (1, 2). Recent findings (e.g., ref. 3), however, have compelled us to move away from a simple view of transmission in the brain, in which glutamate and GABA represent the major excitatory and inhibitory transmitter systems, to a more nuanced interpretation of their roles.GABAergic neurotransmission has both inhibitory and excitatory effects in the CNS. Whereas the inhibitory actions of GABA on principal neurons in different brain regions have been examined extensively, studies of excitatory GABA have focused mostly on the developmental aspects of neuronal growth and synapse formation (4, 5). Recent evidence suggests that GABA can be excitatory in mature neurons as well (with the term “mature” here referring to neurons that are integral parts of established brain networks) (3, 6).Dynamic GABAergic signaling between inhibitory interneurons is less well understood. The common assumption is that GABAergic signaling between these interneurons would lead to disinhibition of principal neurons in a circuit. Excitatory GABA signaling between these interneurons, on the other hand, could serve as a means for amplification of principal cell inhibition. A combination of the two could effectively buffer interneuron firing rates and possibly normalize circuit output in a given area (7).The modularity in brain circuits allows for application of principles gleaned from the study of one defined circuit to other circuits as well. In the olfactory bulb (OB) glomerulus, the GABAergic periglomerular (PG) cells provide a large fraction of the inhibitory drive for information transfer between the olfactory nerve (ON) and mitral cells (MCs), the principal neurons. In this system, the existence of PG–PG synapses has been demonstrated (8), and GABA has been suggested to be depolarizing, yet inhibitory, on these neurons (9). Whether these synapses participate in glomerular signaling either during odor input or during neuromodulation of glomerular output is not yet known.In this paper, we report that GABAergic connections between PG cells have a bimodal effect on excitation depending on the previous activity state of the neurons. Excitation of PG cells by GABA can lead to amplification of glomerular inhibition via GABA-induced GABA release (GIGR). GABA release from PG cells modulates glomerular output on the activation of nicotinic acetylcholine receptors (nAChRs), wherein weak signals from the ON are filtered out while stronger ones are transmitted (10). Our results suggest that bimodal signaling by GABA could be important in determining set points for inhibition thresholds in the glomerular microcircuit.     

Two populations of kainate receptors with separate signaling mechanisms in hippocampal interneurons

Consistent with the epileptogenic and deleterious effects of the potent neurotoxin kainate, the activation of kainate receptors reduces the synaptic inhibition induced by the amino acid gamma-aminobutyric acid (GABA). Extrapolating from these data led to the conclusion that kainate receptors are located presynaptically. However, kainate directly depolarizes the inhibitory interneurons, causing them to fire repeatedly. This effect might indirectly decrease the size of inhibitory postsynaptic currents recorded from pyramidal cells and places in doubt the presynaptic location for kainate receptors. Here we show that both effects, membrane depolarization and the reduction of inhibitory potentials, can be dissociated by several means, particularly by the natural agonist of kainate receptors, glutamate. Indeed, when applied at low concentrations, glutamate inhibited GABA release without affecting the firing rate of GABA interneurons. These results indicate that CA1 interneurons contain two populations of kainate receptors, each with different agonist sensitivity and coupled to distinct signaling pathways.