Response of de- and hyperpolarizing effects in neuronal networks with different mechanisms for terminating activity

The response of stochastically organized homogeneous neuronal networks and others reacting by pre- and postsynaptic inhibition to external de- and hyperpolarizing effects of different intensity and time course were compared using a simulated mathematical computer model. The area of lasting depolarizing effects extended in those with pre- and postsynaptic inhibition compared with heterogeneous neuronal networks. Effects of brief de- and hyperpolarizing effects in a network depended on fluctuations in the level of the activity it displays; depolarizing effects may shorten and hyperpolarizing influences prolong the activity period of networks. The effects of a shortened network activity stage due to brief depolarizing influences was also more marked in networks with preand postsynaptic inhibition. Findings from this research would lead to the deduction that the presence of additional negative feedback circuits in the form of presynaptic or postsynaptic inhibitory series promotes better control in the mechanisms terminating network activity.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 20, No. 4, pp. 438–447, July–August, 1988.     

Mechanisms of establishing long-term fluctuations in the activity of neuronal networks. I. Stochastic uniform neuronal networks

The possibility of generating long-term self-terminating activity lasting some hundreds of milliseconds in neuronal networks with positive (excitatory) feedback was investigated using a computerized mathematical simulation model. This auto-termination is compounded of several factors: stochasticity of the neuronal network, mediating fluctuations in activity level; neuronal interaction, leading either to synchronized discharges and hence of postactivational inhibitory processes, or else to a reorganization of the microstructure underlying neuronal network activity mainly conducive to excitation of neurons with tenuous connections. The likely contribution of these mechanisms to establishing long-term self-terminating activity in the cerebral neuronal networks responsible for different types of programmed rhythmic activity (or generators) is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 18, No. 3, pp. 382–391, May–June, 1986.     

Responses of auditory cortex neurons in unanesthetized cats to best-frequency tones

The characteristics of extra- and intracellular responses of neurons in the AI region were studied in experiments with unanesthetized cats. It was established that auditory cortex neurons with similar best frequencies showed different forms of responses to tones of the corresponding frequency. About 40% of the auditory cortex neurons generated on responses to tone presentation. On — off and off responses were found in 27% of the neurons. Cortical neurons (27%) in which stimulation or inhibition of impulse discharge persisted throughout tone action were assigned to the tonic type group of cells. Approximately 6% of neurons in the AI region did not respond to a tone. During intracellular recording about 85% of the neurons responded to the turning on and/or off of a tone by generating an action potential followed by an IPSI. In 96% of the cortical neurons studied the IPSPs were a constant component of the intracellular responses to a tone. It is concluded that the inhibition of the impulse activity of the given neurons is of primarily a postsynaptic origin. Neurons showing one or another form of response differ from one another in the relative intensity and time characteristics of excitatory and inhibitory processes interacting on their postsynaptic membranes. In neurons of the phasic type inhibitory processes are dominant over excitatory, while excitatory processes are predominant in neurons of the tonic type.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 17, No. 4, pp. 500–508, July–August, 1985.     

Spiking behavior and epileptiform oscillations in a discrete model of cortical neural networks

Summary We investigate the phenomenon of epileptiform activity using a discrete model of cortical neural networks. Our model is reduced to the elementary features of neurons and assumes simplified dynamics of action potentials and postsynaptic potentials. The discrete model provides a comparably high simulation speed which allows the rendering of phase diagrams and simulations of large neural networks in reasonable time. Further the reduction to the basic features of neurons provides insight into the essentials of a possible mechanism of epilepsy. Our computer simulations suggest that the detailed dynamics of postsynaptic and action potentials are not indispensable for obtaining epileptiform behavior on the system level. The simulation results of autonomously evolving networks exhibit a regime in which the network dynamics spontaneously switch between fluctuating and oscillating behavior and produce isolated network spikes without external stimulation. Inhibitory neurons have been found to play an important part in the synchronization of neural firing: an increased number of synapses established by inhibitory neurons onto other neurons induces a transition to the spiking regime. A decreased frequency accompanying the hypersynchronous population activity has only occurred with slow inhibitory postsynaptic potentials.     

NO inhibits supraoptic oxytocin and vasopressin neurons via activation of GABAergic synaptic inputs

To study modulatory actions of nitric oxide (NO) on GABAergic synaptic activity in hypothalamic magnocellular neurons in the supraoptic nucleus (SON), in vitro and in vivo electrophysiological recordings were obtained from identified oxytocin and vasopressin neurons. Whole cell patch-clamp recordings were obtained in vitro from immunochemically identified oxytocin and vasopressin neurons. GABAergic synaptic activity was assessed in vitro by measuring GABA(A) miniature inhibitory postsynaptic currents (mIPSCs). The NO donor and precursor sodium nitroprusside (SNP) and L-arginine, respectively, increased the frequency and amplitude of GABA(A) mIPSCs in both cell types (P < or = 0.001). Retrodialysis of SNP (50 mM) onto the SON in vivo inhibited the activity of both neuronal types (P < or = 0.002), an effect that was reduced by retrodialysis of the GABA(A)-receptor antagonist bicuculline (2 mM, P < or = 0.001). Neurons activated by intravenous infusion of 2 M NaCl were still strongly inhibited by SNP. These results suggest that NO inhibition of neuronal excitability in oxytocin and vasopressin neurons involves pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON.     

Functional Calcium Imaging in Developing Cortical Networks

A hallmark pattern of activity in developing nervous systems is spontaneous, synchronized network activity. Synchronized activity has been observed in intact spinal cord, brainstem, retina, cortex and dissociated neuronal culture preparations. During periods of spontaneous activity, neurons depolarize to fire single or bursts of action potentials, activating many ion channels. Depolarization activates voltage-gated calcium channels on dendrites and spines that mediate calcium influx. Highly synchronized electrical activity has been measured from local neuronal networks using field electrodes. This technique enables high temporal sampling rates but lower spatial resolution due to integrated read-out of multiple neurons at one electrode. Single cell resolution of neuronal activity is possible using patch-clamp electrophysiology on single neurons to measure firing activity. However, the ability to measure from a network is limited to the number of neurons patched simultaneously, and typically is only one or two neurons. The use of calcium-dependent fluorescent indicator dyes has enabled the measurement of synchronized activity across a network of cells. This technique gives both high spatial resolution and sufficient temporal sampling to record spontaneous activity of the developing network.A key feature of newly-forming cortical and hippocampal networks during pre- and early postnatal development is spontaneous, synchronized neuronal activity (Katz & Shatz, 1996; Khaziphov & Luhmann, 2006). This correlated network activity is believed to be essential for the generation of functional circuits in the developing nervous system (Spitzer, 2006). In both primate and rodent brain, early electrical and calcium network waves are observed pre- and postnatally in vivo and in vitro (Adelsberger et al., 2005; Garaschuk et al., 2000; Lamblin et al., 1999). These early activity patterns, which are known to control several developmental processes including neuronal differentiation, synaptogenesis and plasticity (Rakic & Komuro, 1995; Spitzer et al., 2004) are of critical importance for the correct development and maturation of the cortical circuitry.In this JoVE video, we demonstrate the methods used to image spontaneous activity in developing cortical networks. Calcium-sensitive indicators, such as Fura 2-AM ester diffuse across the cell membrane where intracellular esterase activity cleaves the AM esters to leave the cell-impermeant form of indicator dye. The impermeant form of indicator has carboxylic acid groups which are able to then detect and bind calcium ions intracellularly.. The fluorescence of the calcium-sensitive dye is transiently altered upon binding to calcium. Single or multi-photon imaging techniques are used to measure the change in photons being emitted from the dye, and thus indicate an alteration in intracellular calcium. Furthermore, these calcium-dependent indicators can be combined with other fluorescent markers to investigate cell types within the active network.     

Convergence of preganglionic fibers on superior cervical ganglion neurons in the rabbit

Intracellular recording techniques were used to record electrical response from neurons of the rabbit (isolated) superior cervical ganglion to single stimuli applied to bundles of preganglionic fibers as well as tonic electrical neuronal activity in this ganglion during acute experiments in situ. A review of the findings obtained confirms that neurons of the ganglion receive preganglionic synaptic inputs of two types, the first of a single pattern, formed by a preganglionic fiber; excitatory action of the latter on ganglion units suffices to induce postsynaptic action potentials (AP I) and the second of a multiple pattern, formed by several preganglionic fibers with relatively faint excitatory action, capable of evoking postsynaptic action potentials (AP II) only when excited in unison. Interspike intervals for AP I and AP II in tonic neuronal activity conformed to a normal distribution and a random distribution pattern respectively.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 21, No. 2, pp. 252–261, March–April, 1989.     

Changes in membrane potential and postsynaptic potentials evoked by strychnine in neocortical neurons

Intracellular responses of neurons of the suprasylvian fissure to intracortical stimulation before and during topical cortical strychnine application was studied in experiments on immobilized, unanesthetized cats (a local anesthetic was used). Untreated cortical neurons responded to intracortical stimulation with a monosynaptic excitatory postsynaptic potential (EPSP) followed by an inhibitory postsynaptic potential (IPSP). Application of strychnine evoked epileptiform population activity and paroxysmal depolarizations of neuronal membrane potentials (MPs), followed by hyperpolarization. Increased hyperpolarizations, and the prolonged duration of their summation were responsible for an increased MP and reduced or abolished tonic spike activity. Intracellular application (as a result of diffusion from the microelectrode) of ethyleneglycoltetraacetate (EGTA) that blocked the calcium-dependent potassium membrane conductance (gK(Ca)) abolished the hyperpolarization. The development of epileptiform activity was accompanied by reduction of the IPSP, and an increase in the monosynaptic EPSP. The role of gK(Ca) and postsynaptic inhibition in epileptogenesis is discussed.I. I. Mechnikov State University, Odessa. Translated from Neirofiziologiya, Vol. 24, No. 6, pp. 684–691, November–December, 1992.     

Influence of afferent impulses from the nerves of the anterior limbs on the insertion neurons of the lumbar section of the spinal cord

In anesthetized cats in conditions of muscular relaxation we have studied the participation of the interneurons of the lumbar section of the spinal cord in the interaction of the FRA systems of the fore and hind limbs. Using microelectrodes we have made extra- and intracellular recordings of the potentials. It has been shown that from the flexor afferents of the fore limbs both facilitating and inhibitory influences are transmitted. The former are expressed in increased frequency of the background impulse activity of the neurons, in the appearance of evoked responses of the "silent" cells and intensification of the test responses for short time intervals with paired heteronymous stimulation. The inhibitory influences prevail over the facilitating and are manifest in depression of the background activity and evoked segmental responses of the neurons. The maximum inhibition of the segmental responses was noted for intervals of 40–140 msec. The duration of inhibition varied from 100–500 msec and more. Depending on the intensity and duration of the inhibitory influences two groups of interneurons have been isolated. The role of the pre- and postsynaptic mechanisms in the transmission of inhibitory influences from the afferents of the fore limbs on the afferents of the hind limbs is discussed.Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 1, No. 3, pp. 235–242, November–December, 1969.     

Two patterns of bulbar neuronal response to microstimulation of locomotor and inhibitory brain stem sites

Synaptic responses (postsynaptic potentials and action potentials) were evoked in mesencephalic decerebellated cats by stimulating pontine bulbar locomotor and inhibitory sites (LS and IS, respectively) with a current of not more than 20 µA in "medial" and "lateral" neurons of the medulla. Some neurons even produced a response to presentation of single (actually low — 2–5 Hz — frequency) stimuli. The remaining cells responded to stimulation at a steady rate of 30–60 Hz only. Both groups of medial neurons were more receptive to input from LS. Lateral neurons responding to even single stimuli reacted more commonly to input from LS and those responding to steady stimulation only to input from IS. Many neurons with background activity (whether lateral or medial) produced no stimulus-bound response, but rhythmic stimulation either intensified or inhibited such activity. This response occurs most commonly with LS stimulation. Partial redistribution of target neurons in step with increasing rate of presynaptic input may play a major part in control of motor activity.Institute for Research into Information Transmission, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 22, No. 2, pp. 257–266, March–April, 1990.     

Effects of applying electrical stimulation to the locus coeruleus on neuronal activity in the parietal association cortex

It was shown during experiments on cats undergoing surgery under ketamine-induced anesthesia and immobilized with myorelaxin that applying trains of stimuli to the locus coeruleus (LC) produces an effect on 79% of parietal cortex neurons. This manifests as inhibition lasting 300–700 msec or a 16–32% decline in the activity rate of neurons with background activity. Hyperpolarization of 5–7 mV lasting 120–500 msec preceded by a latency of 30–90 msec was noted in such neurons as well as "silent" cells during intracellular recording. Duration of the inhibitory pause in neuronal background activity induced by transcallosal stimulation (TCS) increased by 50–200 msec under the effects of conditioned stimuli applied to the LC. Duration of the IPSP triggered by TCS likewise increased (by 50–100 msec) under the effects of LC stimulation. It was concluded that the effects of stimulating the LC on neuronal activity in the parietal cortex may manifest either directly, as inhibition of background activity and hyperpolarization, or else as modulation of influences exerted by other neurotransmitters.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 22, No. 4, pp. 486–494, July–August, 1990.     

Role of GABAA-Mediated Inhibition and Functional Assortment of Synapses onto Individual Layer 4 Neurons in Regulating Plasticity Expression in Visual Cortex

Layer 4 (L4) of primary visual cortex (V1) is the main recipient of thalamocortical fibers from the dorsal lateral geniculate nucleus (LGN_d). Thus, it is considered the main entry point of visual information into the neocortex and the first anatomical opportunity for intracortical visual processing before information leaves L4 and reaches supra- and infragranular cortical layers. The strength of monosynaptic connections from individual L4 excitatory cells onto adjacent L4 cells (unitary connections) is highly malleable, demonstrating that the initial stage of intracortical synaptic transmission of thalamocortical information can be altered by previous activity. However, the inhibitory network within L4 of V1 may act as an internal gate for induction of excitatory synaptic plasticity, thus providing either high fidelity throughput to supragranular layers or transmittal of a modified signal subject to recent activity-dependent plasticity. To evaluate this possibility, we compared the induction of synaptic plasticity using classical extracellular stimulation protocols that recruit a combination of excitatory and inhibitory synapses with stimulation of a single excitatory neuron onto a L4 cell. In order to induce plasticity, we paired pre- and postsynaptic activity (with the onset of postsynaptic spiking leading the presynaptic activation by 10ms) using extracellular stimulation (ECS) in acute slices of primary visual cortex and comparing the outcomes with our previously published results in which an identical protocol was used to induce synaptic plasticity between individual pre- and postsynaptic L4 excitatory neurons. Our results indicate that pairing of ECS with spiking in a L4 neuron fails to induce plasticity in L4-L4 connections if synaptic inhibition is intact. However, application of a similar pairing protocol under GABA_ARs inhibition by bath application of 2μM bicuculline does induce robust synaptic plasticity, long term potentiation (LTP) or long term depression (LTD), similar to our results with pairing of pre- and postsynaptic activation between individual excitatory L4 neurons in which inhibitory connections are not activated. These results are consistent with the well-established observation that inhibition limits the capacity for induction of plasticity at excitatory synapses and that pre- and postsynaptic activation at a fixed time interval can result in a variable range of plasticity outcomes. However, in the current study by virtue of having two sets of experimental data, we have provided a new insight into these processes. By randomly mixing the assorting of individual L4 neurons according to the frequency distribution of the experimentally determined plasticity outcome distribution based on the calculated convergence of multiple individual L4 neurons onto a single postsynaptic L4 neuron, we were able to compare then actual ECS plasticity outcomes to those predicted by randomly mixing individual pairs of neurons. Interestingly, the observed plasticity profiles with ECS cannot account for the random assortment of plasticity behaviors of synaptic connections between individual cell pairs. These results suggest that connections impinging onto a single postsynaptic cell may be grouped according to plasticity states.     

Synchronization and sensitivity enhancement of the Hodgkin-Huxley neurons due to inhibitory inputs

Recent experimental results imply that inhibitory postsynaptic potentials can play a functional role in realizing synchronization of neuronal firing in the brain. In order to examine the relation between inhibition and synchronous firing of neurons theoretically, we analyze possible effects of synchronization and sensitivity enhancement caused by inhibitory inputs to neurons with a biologically realistic model of the Hodgkin-Huxley equations. The result shows that, after an inhibitory spike, the firing probability of a single postsynaptic neuron exposed to random excitatory background activity oscillates with time. The oscillation of the firing probability can be related to synchronous firing of neurons receiving an inhibitory spike simultaneously. Further, we show that when an inhibitory spike input precedes an excitatory spike input, the presence of such preceding inhibition raises the firing probability peak of the neuron after the excitatory input. The result indicates that an inhibitory spike input can enhance the sensitivity of the postsynaptic neuron to the following excitatory spike input. Two neural network models based on these effects on postsynaptic neurons caused by inhibitory inputs are proposed to demonstrate possible mechanisms of detecting particular spatiotemporal spike patterns. Received: 15 April 1999 /Accepted in revised form: 25 November 1999     

Inhibition in hippocampal pyramidal neurons during peripheral stimulation

Responses of hippocampal pyramidal neurons were investigated intracellularly in unanesthetized rabbits immobilized with tubocurarine. A single stimulus, applied to the sciatic nerve, evoked prolonged (up to 2.5 sec) hyperpolarization of the cell membrane, accompanied by inhibition of action potentials. The latent period of the evoked hyperpolarization was 48±16.4 msec, and its amplitude 2.5±1.9 mV. In some neurons the development of hyperpolarization potentials was preceded by excitation. The suggestion is made that hyperpolarization of the membrane of pyramidal cells during peripheral stimulation is manifested as an inhibitory postsynaptic potential (IPSP), generated with the participation of hippocampal interneurons. The possibility of prolonged tonic action of interneurons from outside as a cause of prolonged inhibition of the pyramidal neurons is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 1, No. 3, pp. 278–284, November–December, 1969.     

NAD causes dissociation of neural networks into subpopulations of neurons by inhibiting the network synchronous hyperactivity evoked by ammonium ions

The mechanisms of hyperexcitability of neuronal networks by ammonium ions and inhibition of this activity by coenzyme NAD were investigated on mixed neuro-glial cultures of rat hippocampus. Ammonium ions cause activation of silent or spontaneously active neuronal networks inducing a bursting electrical activity of neurons and high-frequency synchronous calcium oscillations. In control conditions NAD completely inhibits spontaneous activity of the neuronal network. NAD added after NH₄Cl disrupts synchronous oscillation in neurons and splits the network into five populations of neurons. In 4% of cells NAD decreased the amplitude of Ca²⁺ oscillations, preserving initial mode of oscillations. In 32% of cells, a transient suppression of the neuronal oscillations was observed: inhibition was followed by restoration of the synchronous periodic activity. In 10% of cells, NAD produced a gradual decrease of Ca²⁺ oscillations down to a complete termination of the initial periodic activity induced by ammonium. Fast and total inhibition of Ca²⁺ oscillations by NAD was observed in two small groups of neurons. First group (A) participated in the initial spontaneous network activity (5% of cells) with a period of 66–100 s. Second group (B), on the contrary, did not participate in the spontaneous activity. This group of neurons began to pulse with a high frequency (with a period of 6–8 s) synchronously with other neurons in the network after the addition of NH₄Cl. Based on the comparison of calcium responses of different cell groups to the depolarization caused by KCl and NH₄Cl and to the application of domoic acid, as well as on the results obtained in experiments with fluorescent antibodies against GAD 65/67, parvalbumin, calretinin, and calbindin, we propose that neurons of populations (A) and (B) may belong to GABAergic neurons containing calbindin and parvalbumin, respectively. Further analysis of specificity of the NAD effect on these neuronal groups may allow identification of the main targets of the ammonium toxic action in the brain. Thus, we have shown that NAD selectively inhibits neuronal activity and high-frequency synchronous Ca²⁺ oscillations in GABAergic neurons containing calcium-binding proteins. The inhibition is accompanied by desynchronization of oscillations and dissociation of neuronal network into several populations.     

Efficient and robust coding in heterogeneous recurrent networks

Cortical networks show a large heterogeneity of neuronal properties. However, traditional coding models have focused on homogeneous populations of excitatory and inhibitory neurons. Here, we analytically derive a class of recurrent networks of spiking neurons that close to optimally track a continuously varying input online, based on two assumptions: 1) every spike is decoded linearly and 2) the network aims to reduce the mean-squared error between the input and the estimate. From this we derive a class of predictive coding networks, that unifies encoding and decoding and in which we can investigate the difference between homogeneous networks and heterogeneous networks, in which each neurons represents different features and has different spike-generating properties. We find that in this framework, ‘type 1’ and ‘type 2’ neurons arise naturally and networks consisting of a heterogeneous population of different neuron types are both more efficient and more robust against correlated noise. We make two experimental predictions: 1) we predict that integrators show strong correlations with other integrators and resonators are correlated with resonators, whereas the correlations are much weaker between neurons with different coding properties and 2) that ‘type 2’ neurons are more coherent with the overall network activity than ‘type 1’ neurons.     

Modulation of network activity and induction of homeostatic synaptic plasticity by enzymatic removal of heparan sulfates

Heparan sulfates (HSs) are complex and highly active molecules that are required for synaptogenesis and long-term potentiation. A deficit in HSs leads to autistic phenotype in mice. Here, we investigated the long-term effect of heparinase I, which digests highly sulfated HSs, on the spontaneous bioelectrical activity of neuronal networks in developing primary hippocampal cultures. We found that chronic heparinase treatment led to a significant reduction of the mean firing rate of neurons, particularly during the period of maximal neuronal activity. Furthermore, firing pattern in heparinase-treated cultures often appeared as epileptiform bursts, with long periods of inactivity between them. These changes in network activity were accompanied by an increase in the frequency and amplitude of miniature postsynaptic excitatory currents, which could be described by a linear up-scaling of current amplitudes. Biochemically, we observed an upregulation in the expression of the glutamate receptor subunit GluA1, but not GluA2, and a strong increase in autophosphorylation of α and β Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), without changes in the levels of kinase expression. These data suggest that a deficit in HSs triggers homeostatic synaptic plasticity and drastically affects functional maturation of neural network.     

A possible mechanism of influence of modifiable striatal lateral inhibition on the conditioned selection of motor activity

A mechanism of the influence of dopamine-evoked modulation of lateral inhibition in the striatum on a conditioned selection of motor activity is proposed. According to suggested modulation rules for inhibitory transmission, action of dopamine on postsynaptic D1 (D2) receptors on striatonigral (striatopallidal) cells promotes long-term depression (potentiation) of inhibitory inputs simultaneously with potentiation (depression) of "strong" excitatory inputs that open NMDA channels on these neurons. If excitatory inputs are "weak" and NMDA channels are closed, modulation rules have opposite signs. Activation of presynaptic D2 (D1) receptors results in a decrease (increase) in GABA release from striatopallidal (striatonigral) axon terminals that innervate striatonigral (striatopallidal) cells. Thereof, dopamine-evoked modulation of lateral inhibition simultaneously strengthens both potentiation (depression) of excitatory inputs to "strongly" activated striatonigral (striatopallidal) neurons rising (reducing) their activity, and depression (potentiation) of excitatory inputs to "weakly" activated striatonigral (striatopallidal) neurons reducing (rising) their activity. Subsequent reorganization of neuronal activity in the cortico-basal-ganglia-thalamocortical loop promotes a conditioned selection of motor reaction because of the further increase (decrease) in activity of those motocortical neurons that "strongly" ("weakly") activated the striatum during dopamine release in response to conditioned stimulus.     

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.     

Brief Subthreshold Events Can Act as Hebbian Signals for Long-Term Plasticity

Background

Action potentials are thought to be determinant for the induction of long-term synaptic plasticity, the cellular basis of learning and memory. However, neuronal activity does not lead systematically to an action potential but also, in many cases, to synaptic depolarizing subthreshold events. This is particularly exemplified in corticostriatal information processing. Indeed, the striatum integrates information from the whole cerebral cortex and, due to the membrane properties of striatal medium spiny neurons, cortical inputs do not systematically trigger an action potential but a wide range of subthreshold postsynaptic depolarizations. Accordingly, we have addressed the following question: does a brief subthreshold event act as a Hebbian signal and induce long-term synaptic efficacy changes?

Methodology/Principal Findings

Here, using perforated patch-clamp recordings on rat brain corticostriatal slices, we demonstrate, that brief (30 ms) subthreshold depolarizing events in quasi-coincidence with presynaptic activity can act as Hebbian signals and are sufficient to induce long-term synaptic plasticity at corticostriatal synapses. This “subthreshold-depolarization dependent plasticity” (SDDP) induces strong, significant and bidirectional long-term synaptic efficacy changes at a very high occurrence (81%) for time intervals between pre- and postsynaptic stimulations (Δt) of −110<Δt<+110 ms. Such subthreshold depolarizations are able to induce robust long-term depression (cannabinoid type-1 receptor-activation dependent) as well as long-term potentiation (NMDA receptor-activation dependent).

Conclusion/Significance

Our data show the existence of a robust, reliable and timing-dependent bidirectional long-term plasticity induced by brief subthreshold events paired with presynaptic activity. The existence of a subthreshold-depolarization dependent plasticity extends considerably, beyond the action potential, the neuron''s capabilities to express long-term synaptic efficacy changes.