Synaptic interactions between nonspiking local interneurones in the terminal abdominal ganglion of the crayfish

Nonspiking local interneurones are the important premotor elements in arthropod motor control systems. We have analyzed the synaptic interactions between nonspiking interneurones in the crayfish terminal (6th) abdominal ganglion using simultaneous intracellular recordings. Only 15% of nonspiking interneurones formed bi-directional excitatory connections. In 77% of connections, however, the nonspiking interneurones showed a one-way inhibitory interaction. In these cases, the presynaptic nonspiking interneurones received excitatory synaptic inputs from the sensory afferents innervating hairs on the surface of the uropods and the postsynaptic nonspiking interneurones received inhibitory synaptic inputs that were partly mediated by the inputs to the presynaptic nonspiking interneurones. The membrane hyperpolarization of the postsynaptic nonspiking interneurones mediated by the presynaptic nonspiking interneurones was reduced in amplitude when the hyperpolarizing current was injected into the postsynaptic interneurones, or when the external bathing solution was replaced with one containing low calcium and high magnesium concentrations. The role of these interactions in the circuits controlling the movements of the terminal appendages is discussed.Abbreviations AL antero-lateral - epsp excitatory postsynaptic potential - ipsp inhibitory postsynaptic potential - PL postero-lateral     

Opioid inhibition of GABA release from presynaptic terminals of rat hippocampal interneurons.

Opiates and the opioid peptide enkephalin can cause indirect excitation of principal cortical neurons by reducing inhibitory synaptic transmission mediated by GABAergic interneurons. The mechanism by which opioids mediate these effects on interneurons is unknown, but enkephalin hyperpolarizes the somatic membrane potential of a variety of neurons in the brain, including hippocampal interneurons. We now report a new, more direct mechanism for the opioid-mediated reduction in synaptic inhibition. The enkephalin analog D-Ala2-Met5-enkephalinamide (DALA) decreases the frequency of miniature, action potential-independent, spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) without causing a change in their amplitude. Thus, we conclude that DALA inhibits the action potential-independent release of GABA through a direct action on interneuronal synaptic terminals. In contrast, DALA reduces the amplitude of action potential-evoked, GABA-mediated IPSCs, as well as decreases their frequency. This suggests that the opioid-mediated inhibition of non-action potential-dependent GABA release reveals a mechanism that contributes to reducing action potential-evoked GABA release, thereby decreasing synaptic inhibition.     

Role of local nonspiking interneurons in the generation of rhythmic motor activity in the stick insect

Local nonspiking interneurons in the thoracic ganglia of insects are important premotor elements in posture control and locomotion. It was investigated whether these interneurons are involved in the central neuronal circuits generating the oscillatory motor output of the leg muscle system during rhythmic motor activity. Intracellular recordings from premotor nonspiking interneurons were made in the isolated and completely deafferented mesothoracic ganglion of the stick insect in preparations exhibiting rhythmic motor activity induced by the muscarinic agonist pilocarpine. All interneurons investigated provided synaptic drive to one or more motoneuron pools supplying the three proximal leg joints, that is, the thoraco-coxal joint, the coxa-trochanteral joint and the femur-tibia joint. During rhythmicity in 83% (n=67) of the recorded interneurons, three different kinds of synaptic oscillations in membrane potential were observed: (1) Oscillations were closely correlated with the activity of motoneuron pools affected; (2) membrane potential oscillations reflected only certain aspects of motoneuronal rhythmicity; and (3) membrane potential oscillations were correlated mainly with the occurrence of spontaneous recurrent patterns (SRP) of activity in the motoneuron pools. In individual interneurons membrane potential oscillations were associated with phase-dependent changes in the neuron's membrane conductance. Artificial changes in the interneurons' membrane potential strongly influenced motor activity. Injecting current pulses into individual interneurons caused a reset of rhythmicity in motoneurons. Furthermore, current injection into interneurons influenced shape and probability of occurrence for SRPs. Among others, identified nonspiking interneurons that are involved in posture control of leg joints were found to exhibit the above properties. From these results, the following conclusions on the role of nonspiking interneurons in the generation of rhythmic motor activity, and thus potentially also during locomotion, emerge: (1) During rhythmic motor activity most nonspiking interneurons receive strong synaptic drive from central rhythm-generating networks; and (2) individual nonspiking interneurons some of which underlie sensory-motor pathways in posture control, are elements of central neuronal networks that generate alternating activity in antagonistic leg motoneuron pools. © 1995 John Wiley & Sons, Inc.     

Neuropharmacology of supraoptic nucleus neurons: norepinephrine and gamma-aminobutyric acid receptors

The neurosecretory neurons in the mammalian hypothalamic supraoptic nucleus receive prominent GABAergic and noradrenergic projections arising from local interneurons and the A1 cells in the ventrolateral medulla, respectively. Intracellular recordings in in vitro perfused hypothalamic explants reveal an abundance of spontaneous inhibitory postsynaptic potentials (IPSPs) and a compound IPSP after electrical stimulation in the diagonal band of Broca area. The sensitivity of both spontaneous and evoked IPSPs to intracellular chloride injection, bicuculline, and pentobarbital is consistent with a GABA-activated, chloride-mediated inhibitory synaptic input. Parallel changes in membrane voltage and conductance are present during applications of GABA and muscimol, with similar sensitivity to ionic manipulation, bicuculline, and pentobarbital. These observations contrast with the consistently excitatory effects that follow either the stimulation of A1 cells or the application of norepinephrine and alpha 1-adrenergic agonists. Norepinephrine induces membrane depolarizations and bursting activity patterns that are blocked by the selective alpha 1 antagonist prazosin. Membrane response to norepinephrine is voltage dependent and is associated with little change in conductance. GABA and norepinephrine are proposed as transmitters in the final central pathways that mediate information to supraoptic vasopressinergic neurons from peripheral baroreceptors and chemoreceptors, respectively.     

GABA and neuroligin signaling: linking synaptic activity and adhesion in inhibitory synapse development

GABA-mediated synaptic inhibition is crucial in neural circuit operations. In mammalian brains, the development of inhibitory synapses and innervation patterns is often a prolonged postnatal process, regulated by neural activity. Emerging evidence indicates that gamma-aminobutyric acid (GABA) acts beyond inhibitory transmission and regulates inhibitory synapse development. Indeed, GABA(A) receptors not only function as chloride channels that regulate membrane voltage and conductance but also play structural roles in synapse maturation and stabilization. The link from GABA(A) receptors to postsynaptic and presynaptic adhesion is probably mediated, partly by neuroligin-reurexin interactions, which are potent in promoting GABAergic synapse formation. Therefore, similar to glutamate signaling at excitatory synapse, GABA signaling may coordinate maturation of presynaptic and postsynaptic sites at inhibitory synapses. Defining the many steps from GABA signaling to receptor trafficking/stability and neuroligin function will provide further mechanistic insights into activity-dependent development and possibly plasticity of inhibitory synapses.     

Dendritic properties of uropod motoneurons and premotor nonspiking interneurons in the crayfish Procambarus clarkii Girard

Dendritic properties of uropod motoneurons and premotor nonspiking interneurons of crayfish have been studied using intradendritic recording and current injection. The input resistance of phasic motoneurons (5.20 ± 0.5 M; mean ± standard error) measured by injecting constant hyperpolarizing current was significantly lower than that of tonic motoneurons (10.3 ± 2.6 M; 0.02 < P < 0.05). The membrane time constant of phasic motoneurons (7.3 ± 0.9 ms) was also significantly shorter than that of tonic motoneurons (24.3 ± 2.5 ms; P < 0.001). Both types of motoneurons behaved linearly during hyperpolarization and sub-threshold depolarization. Nonspiking interneurons showed outward rectification upon depolarization. During hyperpolarization, their membrane behaved linearly and showed significantly higher input resistance (19.5 ± 2.5 M) than phasic and tonic motoneurons (P < 0.001). Their membrane time constant (38.0 ± 5.7 ms) was significantly longer than that of phasic motoneurons (P < 0.001) but not than that of tonic motoneurons (P > 0.05). In response to intracellular injection of sinusoidally oscillating current, phasic motoneurons showed one or two spikes per depolarization period irrespective of oscillating frequency ranging from 1 to 16 Hz. Tonic motoneurons showed larger numbers of spikes per stimulus period at lower frequencies. Nonspiking interneurons also showed phase-locked effects on the motoneuron spike activity. The effective frequency range over which injected oscillating current could modulate motoneuron spike activity was similar for tonic motoneurons and nonspiking interneurons.     

Presynaptic Modulation by Somatostatin in the Neostriatum

Medium spiny projection neurons (MSNs) are the main neuronal population in the neostriatum. MSNs are inhibitory and GABAergic. MSNs connect with other MSNs via local axon collaterals that produce lateral inhibition, which is thought to select cell assemblies for motor action. MSNs also receive inhibitory inputs from GABAergic local interneurons. This work shows, through the use of the paired pulse protocol, that somatostatin (SST) acts presynaptically to regulate GABA release from the terminals interconnecting MSNs. This SST action is reversible and not mediated through the release of dopamine. It is blocked by the SST receptor (SSTR) antagonist ciclosomatostatin (cicloSST). In contrast, SST does not regulate inhibition coming from interneurons. Because, SST is released by a class of local interneuron, it is concluded that this neuron helps to regulate the selection of motor acts. Special issue article in honor of Dr. Ricardo Tapia.     

Non-monotonic effects of GABAergic synaptic inputs on neuronal firing

GABA is generally known as the principal inhibitory neurotransmitter in the nervous system, usually acting by hyperpolarizing membrane potential. However, GABAergic currents sometimes exhibit non-inhibitory effects, depending on the brain region, developmental stage or pathological condition. Here, we investigate the diverse effects of GABA on the firing rate of several single neuron models, using both analytical calculations and numerical simulations. We find that GABAergic synaptic conductance and output firing rate exhibit three qualitatively different regimes as a function of GABA reversal potential, E_GABA: monotonically decreasing for sufficiently low E_GABA (inhibitory), monotonically increasing for E_GABA above firing threshold (excitatory); and a non-monotonic region for intermediate values of E_GABA. In the non-monotonic regime, small GABA conductances have an excitatory effect while large GABA conductances show an inhibitory effect. We provide a phase diagram of different GABAergic effects as a function of GABA reversal potential and glutamate conductance. We find that noisy inputs increase the range of E_GABA for which the non-monotonic effect can be observed. We also construct a micro-circuit model of striatum to explain observed effects of GABAergic fast spiking interneurons on spiny projection neurons, including non-monotonicity, as well as the heterogeneity of the effects. Our work provides a mechanistic explanation of paradoxical effects of GABAergic synaptic inputs, with implications for understanding the effects of GABA in neural computation and development.     

The role of calcium in prolonged modification of a GABAergic synapse.

Caudal hair cell impulses cause postsynaptic inhibition of ipsilateral type B photoreceptors in the snail Hermissenda. This inhibition is shown to be GABAergic according to a number of criteria. HPLC, mass spectrophotometric, and immunocytochemical techniques demonstrated the presence of GABA in the hair cells and their axons. GABA agonists and antagonists mimic and block the synaptic effect in a manner consistent with endogenous GABAergic transmission. Other properties, including I-V relations, conductance changes and reversal potentials, are comparable for exogenous GABA responses and endogenous effects of the hair cell impulses. This inhibitory synapse has been found to undergo a long-lasting transformation into an excitatory synapse if GABA release is paired with post-synaptic depolarization. GABA, via GABAA and GABAB receptors in the B cell, causes the opening of calcium sensitive chloride and potassium channels that leads to the post-synaptic hyperpolarization. GABA also induces a long-lasting intracellular calcium elevation at the terminal branches of the B cell that greatly outlasts the voltage responses. Synaptic transformation induced by pairings is caused by a decrease in both GABA induced chloride and potassium conductances in the post-synaptic B cell, as well as a significant prolongation of the intracellular calcium accumulation in the B cell's terminal axonal branches.     

GABA-mediated synaptic inhibition of projection neurons in the antennal lobes of the sphinx moth,Manduca sexta

Responses of neurons in the antennal lobe (AL) of the moth Manduca sexta to stimulation of the ipsilateral antenna by odors consist of excitatory and inhibitory synaptic potentials. Stimulation of primary afferent fibers by electrical shock of the antennal nerve causes a characteristic IPSP-EPSP synaptic response in AL projection neurons. The IPSP in projection neurons reverses below the resting potential, is sensitive to changes in external and internal chloride concentration, and thus is apparently mediated by an increase in chloride conductance. The IPSP is reversibly blocked by 100 microM picrotoxin or bicuculline. Many AL neurons respond to application of GABA with a strong hyperpolarization and an inhibition of spontaneous spiking activity. GABA responses are associated with an increase in neuronal input conductance and a reversal potential below the resting potential. Application of GABA blocks inhibitory synaptic inputs and reduces or blocks excitatory inputs. EPSPs can be protected from depression by application of GABA. Muscimol, a GABA analog that mimics GABA responses at GABAA receptors but not at GABAB receptors in the vertebrate CNS, inhibits many AL neurons in the moth.     

Activation of subfornical organ neurons in rats through pre- and postsynaptic alpha-adrenoceptors

The effects of noradrenaline (NA) and its analogs on subfornical organ (SFO) neurons in rat slice preparations were investigated by using whole cell patch-clamp recording. In the current-clamp mode, the application of NA at 10-100 microM produced membrane depolarization (63%, 17 responsive neurons/27 neurons tested) and hyperpolarization (22%, 6/27 neurons). In the voltage-clamp mode, NA application at 1-100 microM produced inward currents (69%, 42/61 neurons) and outward currents (23%, 14/61 neurons). These currents remained in the presence of TTX or both glutamate and GABA receptor antagonists. In most of the neurons (25/31 neurons) showing inward currents in the presence of NA, the membrane conductance was not changed by voltage ramps or hyperpolarizing pulse stimulation. Similar responses were obtained by the application of the alpha1-agonist phenylephrine. The phenylephrine-induced inward currents were inhibited by the alpha1-antagonist prazosin. The alpha2-agonist clonidine decreased the frequency of spontaneous GABAergic inhibitory postsynaptic currents (4/10 neurons). In addition, RT-PCR assay and immunohistochemical staining showed the existence of alpha1-adrenoceptors in the SFO. The results suggest that SFO neurons in rats are activated postsynaptically through alpha1-adrenoceptors and that the activation is enhanced by suppressing GABAergic inhibitory synaptic inputs through presynaptic alpha2-adrenoceptors.     

Multiple gate control of the descending statocyst-motor pathway in the crayfish Procambarus clarkii Girard

1. Synaptic responses of uropod motoneurons and interneurons to magnetic field stimulation of the statocyst were studied in a whole animal preparation using intracellular recording and staining techniques to characterize the descending statocyst pathways controlling uropod steering behavior. 2. When the animal was engaged in abdominal postural movement, all uropod motoneurons received sustained excitatory input. Motoneurons which were to be activated during steering behavior showed excitatory responses to the stimulus superimposed on the sustained excitation. In the resting state, they showed weaker responses or no visible responses to the same stimulation. 3. Motoneurons to be suppressed during steering showed inhibitory responses to the stimulus only during abdominal movement. These included both active inhibition as well as disfacilitatory suppression of excitatory input to the motoneurons. 4. Premotor nonspiking interneurons, like motoneurons, showed greater responses to the stimulus during abdominal movement than at rest. Unlike motoneurons, however, they did not always receive sustained input during abdominal movement. 5. Descending axons which responded to statocyst stimulation independent of abdominal movement were found in the 4th and 5th abdominal ganglia. Other axons showed greater responses during abdominal movement than at rest. 6. A number of intersegmental descending interneurons with cell bodies and dendrites in the 4th or 5th ganglion were found to receive excitatory inputs from both the statocyst and the motor system controlling abdominal posture. These responses were found to summate with each other to generate spikes. 7. Statocyst signals are thus transmitted to uropod motoneurons by two types of descending pathways: one whose operation is affected by the abdominal system and the other which operates independently. The former pathway functions by recruiting intersegmental abdominal interneurons and makes stronger connections with motoneurons than the latter.     

Effects of GABA on electrical properties of cultured rat pituitary tumor cells: An intracellular recording study

In this study we show that the electrophysiological properties of a clonal line of prolactin secreting (PRL) rat pituitary cells (GH3/B6) are altered by local application of γ-aminobutyric acid (GABA). The effects of GABA on these cells are: 1) decrease in membrane conductance and 2) hyperpolarization of 5 to 10 mV. When the cells were spontaneously active, GABA reduced and usually arrested action potential firing. This effect was completely reversible. No desensitization of GABA effects was observed even after several applications. The reversal potential of the GABA induced responses was found to be near — 40 mV. Pharmacological studies were performed in order to assess the specificity of the response to GABA and to attempt to characterize the ionic mechanism involved. GABAergic receptor antagonists such as picrotoxin and bicuculline prevented the effect of GABA, whereas dopaminergic receptor antagonists, such as haloperidol or chlorpromazine had no effect. Furosemide, known as a blocker of chloride ion transport in a number of systems, competed with GABA. This substance induced a response similar to that observed with GABA and reduced the effect of GABA when administered before GABA. This study demonstrates a direct and specific effect of GABA on the electrical activity of a tumoral line of rat pituitary cells. Since this electrical activity has previously been shown to be calcium dependent and involved in the secretion of PRL by these cells, the data presented here suggest GABA as an inhibitory regulator of PRL secretion directly at the pituitary level.     

GABA regulates the buccal motor output of Helisoma by two pharmacologically distinct actions

GABA was tested for its effects on patterned motor activity (PMA) underlying feeding. Using buccal motoneuron B19 to monitor PMA through intracellular recordings, GABA was found to exert effects at two levels. First, GABA stimulated rhythmic patterned activity resembling fictive feeding, which is under the control of the buccal CPG. In addition, GABA produced a direct inhibition of neuron B19. Both effects were observed when the buccal ganglia were studied in isolation from the rest of the central nervous system, suggesting local interactions with GABA receptors of buccal neurons. Furthermore, these two actions of GABA were found to be pharmacologically distinguishable. The direct hyperpolarization of neuron B19 was mimicked by muscimol, but not baclofen, and involved an increased chloride conductance, which was blocked by picrotoxin.Baclofen duplicated CPG activation by GABA. Picrotoxin had no effect on GABA- or baclofen-induced PMA.These results demonstrate that the Helisoma buccal ganglia have two GABA receptor types which resemble, pharmacologically, mammalian GABA_A and GABA_B receptors, and that GABA plays a key role in feeding patterned motor activity in Helisoma.Abbreviations CPG central pattern generator - GABA gammaamino butyric acid - HPLC high performance liquid chromatography - IPSP inhibitory postsynaptic potential - PMA patterned motor activity - SLRT supralateral radular tensor muscle     

Ethanol potentiates the effect of gamma-aminobutyric acid on medial vestibular nucleus neurons responding to horizontal rotation

Electrophysiological studies were performed to determine whether or not ethanol potentiates the inhibitory effects of gamma-aminobutyric acid (GABA) on medial vestibular nucleus (MVN) neurons responding to horizontal sinusoidal rotation using alpha-chloralose anesthetized cats. The MVN neurons were classified into types I, II, III and IV neurons according to the responses to the horizontal rotation of the animal placed on the turntable in directions ipsilateral and contralateral to the recording site. In addition, the effects of ethanol and GABA on type I neurons were also examined. Micro-osmotic application of ethanol up to 100 nA did not affect the spontaneous firing or the rotation-induced increase in firing of type I neurons. However, the inhibitory effects of GABA up to 50 nA on the rotation-induced increase in firing were potentiated during simultaneous application of ethanol up to 100 nA. This potentiated inhibition was blocked by iontophoretic application of bicuculline (25-150 nA) and picrotoxin (45-150 nA). These results suggest that ethanol potentiates the inhibitory effects of GABA on MVN type I neurons by acting on the GABA receptor and/or receptor-coupled chloride ion channel.     

Exchange diffusion,electrodiffusion and rectification in the chloride transport pathway of frog skin

Measurements of chloride flux ratios across frog skin at different clamping voltages showed that chloride transport at clamping voltages from 0 mV to and beyond the spontaneous potential is probably electrodiffusion. At reversed potentials a significant fraction of chloride transport could be described formally as exchange diffusion. Chloride conductance was found to be highly voltage dependent, being largest at hyperpolarizing clamping voltages. The transition from the less conducting state to the more conducting one was studied by recording the time course of the current after a step change in clamping voltage from 0 mV to hyperpolarizing voltages. The shape of the curve is sigmoidal, and the relative rate of change of current increases with increasing hyperpolarization. It is proposed that the change in conductance is governed by the same mechanism as in the toad skin, namely a change in chloride permeability due to voltage gating of chloride channels. The time course of transepithelial conductance after addition of amiloride to the outside solution indicates that a fraction of the decrease in conductance is due to closure of chloride channels caused by the change in intracellular potential due to the inhibition of the sodium channels.     

Presynaptic kainate receptors that enhance the release of GABA on CA1 hippocampal interneurons

We report that kainate receptors are present on presynaptic GABAergic terminals contacting interneurons and that their activation increases GABA release. Application of kainate increased the frequency of miniature inhibitory postsynaptic currents recorded in CA1 interneurons. Local applications of glutamate but not of AMPA or NMDA also increased GABA quantal release. Application of kainate as well as synaptically released glutamate reduced the number of failures of GABAergic neurotransmission between interneurons. Thus, activation of presynaptic kainate receptors increases the probability of GABA release at interneuron-interneuron synapses. Glutamate may selectively control the communication between interneurons by increasing their mutual inhibition.     

Distributed processing on the basis of parallel and antagonistic pathways simulation of the femur-tibia control system in the stick insect

In inactive stick insects, sensory information from the femoral chordotonal organ (fCO) about position and movement of the femur-tibia joint is transferred via local nonspiking interneurons onto extensor and flexor tibiae motoneurons. Information is processed by the interaction of antagonistic parallel pathways at two levels: (1) at the input side of the nonspiking interneurons and (2) at the input side of the motoneurons. We tested by a combination of physiological experiments and computer simulation whether the known network topology and the properties of its elements are sufficient to explain the generation of the motor output in response to passive joint movements, that is resistance reflexes. In reinvestigating the quantitative characteristics of interneuronal pathways we identified 10 distinct types of nonspiking interneurons. Synaptic inputs from fCO afferents onto these interneurons are direct excitatory and indirect inhibitory. These connections were investigated with respect to position and velocity signals from the fCO. The results were introduced in the network simulation. The motor output of the simulation has the same characteristics as the real system, even when particular types of interneurons were removed in the simulation and the real system.     

Physiological characteristics of the synaptic response of an identified sensory nonspiking interneuron in the crayfish Procambarus clarkii girard

Voltage-dependent variability in the shape of synaptic responses of the LDS interneuron, an identified nonspiking cell of crayfish, to mechanosensory stimulation was studied using intracellular recording and current injection techniques. Stimulation of the sensory root ipsilateral to the interneuron soma evoked a large depolarizing synaptic response. Its peak amplitude was decreased and the time course was shortened when the LDS interneuron was depolarized by current injection. When the cell was hyperpolarized, the peak amplitude was increased and the time course was prolonged. Upon large hyperpolarization, however, the amplitude did not increase further while the time course showed a slight decrease. The dendritic membrane of the LDS interneuron was found to show an outward rectification upon depolarization and an inward rectification upon large hyperpolarization. Current injection experiments at varying membrane potentials revealed that the voltage-dependent changes in the shape of the synaptic response were based on an increase in membrane conductance due to the rectifying properties of the LDS interneuron. Stimulation of the contralateral root evoked a small depolarizing potential comprising an early excitatory response and a later inhibitory component. Its shape also varied depending on the membrane potential in a manner similar to that of the synaptic response evoked ipsilaterally.     

Inhibitory or excitatory? Optogenetic interrogation of the functional roles of GABAergic interneurons in epileptogenesis

Alteration in the excitatory/inhibitory neuronal balance is believed to be the underlying mechanism of epileptogenesis. Based on this theory, GABAergic interneurons are regarded as the primary inhibitory neurons, whose failure of action permits hyperactivity in the epileptic circuitry. As a consequence, optogenetic excitation of GABAergic interneurons is widely used for seizure suppression. However, recent evidence argues for the context-dependent, possibly “excitatory” roles that GABAergic cells play in epileptic circuitry. We reviewed current optogenetic approaches that target the “inhibitory” roles of GABAergic interneurons for seizure control. We also reviewed interesting evidence that supports the “excitatory” roles of GABAergic interneurons in epileptogenesis. GABAergic interneurons can provide excitatory effects to the epileptic circuits via several distinct neurological mechanisms. (1) GABAergic interneurons can excite postsynaptic neurons, due to the raised reversal potential of GABA receptors in the postsynaptic cells. (2) Continuous activity in GABAergic interneurons could lead to transient GABA depletion, which prevents their inhibitory effect on pyramidal cells. (3) GABAergic interneurons can synchronize network activity during seizure. (4) Some GABAergic interneurons inhibit other interneurons, causing disinhibition of pyramidal neurons and network hyperexcitability. The dynamic, context-dependent role that GABAergic interneurons play in seizure requires further investigation of their functions at single cell and circuitry level. New optogenetic protocols that target GABAergic inhibition should be explored for seizure suppression.