Interplay of Intrinsic and Synaptic Conductances in the Generation of High-Frequency Oscillations in Interneuronal Networks with Irregular Spiking

High-frequency oscillations (above 30 Hz) have been observed in sensory and higher-order brain areas, and are believed to constitute a general hallmark of functional neuronal activation. Fast inhibition in interneuronal networks has been suggested as a general mechanism for the generation of high-frequency oscillations. Certain classes of interneurons exhibit subthreshold oscillations, but the effect of this intrinsic neuronal property on the population rhythm is not completely understood. We study the influence of intrinsic damped subthreshold oscillations in the emergence of collective high-frequency oscillations, and elucidate the dynamical mechanisms that underlie this phenomenon. We simulate neuronal networks composed of either Integrate-and-Fire (IF) or Generalized Integrate-and-Fire (GIF) neurons. The IF model displays purely passive subthreshold dynamics, while the GIF model exhibits subthreshold damped oscillations. Individual neurons receive inhibitory synaptic currents mediated by spiking activity in their neighbors as well as noisy synaptic bombardment, and fire irregularly at a lower rate than population frequency. We identify three factors that affect the influence of single-neuron properties on synchronization mediated by inhibition: i) the firing rate response to the noisy background input, ii) the membrane potential distribution, and iii) the shape of Inhibitory Post-Synaptic Potentials (IPSPs). For hyperpolarizing inhibition, the GIF IPSP profile (factor iii)) exhibits post-inhibitory rebound, which induces a coherent spike-mediated depolarization across cells that greatly facilitates synchronous oscillations. This effect dominates the network dynamics, hence GIF networks display stronger oscillations than IF networks. However, the restorative current in the GIF neuron lowers firing rates and narrows the membrane potential distribution (factors i) and ii), respectively), which tend to decrease synchrony. If inhibition is shunting instead of hyperpolarizing, post-inhibitory rebound is not elicited and factors i) and ii) dominate, yielding lower synchrony in GIF networks than in IF networks.     

Heartbeat control in the medicinal leech: A model system for understanding the origin,coordination, and modulation of rhythmic motor patterns

We have analyzed in detail the neuronal network that generates heartbeat in the leech. Reciprocally inhibitory pairs of heart interneurons form oscillators that pace the heartbeat rhythm. Other heart interneurons coordinate these oscillators. These coordinating interneurons, along with the oscillator interneurons, form an eight-cell timing oscillator network for heartbeat. Still other interneurons, along with the oscillator interneurons, inhibit heart motor neurons, sculpting their activity into rhythmic bursts. Critical switch interneurons interface between the oscillator interneurons and the other premotor interneurons to produce two alternating coordination states of the motor neurons. The periods of the oscillator interneurons are modulated by endogenous RFamide neuropeptides. We have explored the ionic currents and graded and spike-mediated synaptic transmission that promote oscillation in the oscillator interneurons and have incorporated these data into a conductance-based computer model. This model has been of considerable predictive value and has led to new insights into how reciprocally inhibitory neurons produce oscillation. We are now in a strong position to expand this model upward, to encompass the entire heartbeat network, horizontally, to elucidate the mechanisms of FMRFamide modulation, and downward, to incorporate cellular morphology. By studying the mechanisms of motor pattern formation in the leech, using modeling studies in conjunction with parallel physiological experiments, we can contribute to a deeper understanding of how rhythmic motor acts are generated, coordinated, modulated, and reconfigured at the level of networks, cells, ionic currents, and synapses. © 1995 John Wiley & Sons, Inc.     

Synaptic responses evoked by tactile stimuli in Purkinje cells in mouse cerebellar cortex Crus II in vivo

Background

Sensory stimuli evoke responses in cerebellar Purkinje cells (PCs) via the mossy fiber-granule cell pathway. However, the properties of synaptic responses evoked by tactile stimulation in cerebellar PCs are unknown. The present study investigated the synaptic responses of PCs in response to an air-puff stimulation on the ipsilateral whisker pad in urethane-anesthetized mice.

Methods and Main Results

Thirty-three PCs were recorded from 48 urethane-anesthetized adult (6–8-week-old) HA/ICR mice by somatic or dendritic patch-clamp recording and pharmacological methods. Tactile stimulation to the ipsilateral whisker pad was delivered by an air-puff through a 12-gauge stainless steel tube connected with a pressurized injection system. Under current-clamp conditions (I = 0), the air-puff stimulation evoked strong inhibitory postsynaptic potentials (IPSPs) in the somata of PCs. Application of SR95531, a specific GABA_A receptor antagonist, blocked IPSPs and revealed stimulation-evoked simple spike firing. Under voltage-clamp conditions, tactile stimulation evoked a sequence of transient inward currents followed by strong outward currents in the somata and dendrites in PCs. Application of SR95531 blocked outward currents and revealed excitatory postsynaptic currents (EPSCs) in somata and a temporal summation of parallel fiber EPSCs in PC dendrites. We also demonstrated that PCs respond to both the onset and offset of the air-puff stimulation.

Conclusions

These findings indicated that tactile stimulation induced asynchronous parallel fiber excitatory inputs onto the dendrites of PCs, and failed to evoke strong EPSCs and spike firing in PCs, but induced the rapid activation of strong GABA_A receptor-mediated inhibitory postsynaptic currents in the somata and dendrites of PCs in the cerebellar cortex Crus II in urethane-anesthetized mice.     

Mechanisms of postinhibitory rebound and its modulation by serotonin in excitatory swim motor neurons of the medicinal leech

Postinhibitory rebound (PIR) is defined as membrane depolarization occurring at the offset of a hyperpolarizing stimulus and is one of several intrinsic properties that may promote rhythmic electrical activity. PIR can be produced by several mechanisms including hyperpolarization-activated cation current (I_h) or deinactivation of depolarization-activated inward currents. Excitatory swim motor neurons in the leech exhibit PIR in response to injected current pulses or inhibitory synaptic input. Serotonin, a potent modulator of leech swimming behavior, increases the peak amplitude of PIR and decreases its duration, effects consistent with supporting rhythmic activity. In this study, we performed current clamp experiments on dorsal excitatory cell 3 (DE-3) and ventral excitatory cell 4 (VE-4). We found a significant difference in the shape of PIR responses expressed by these two cell types in normal saline, with DE-3 exhibiting a larger prolonged component. Exposing motor neurons to serotonin eliminated this difference. Cs⁺ had no effect on PIR, suggesting that I_h plays no role. PIR was suppressed completely when low Na⁺ solution was combined with Ca²⁺ -channel blockers. Our data support the hypothesis that PIR in swim motor neurons is produced by a combination of low-threshold Na⁺ and Ca²⁺ currents that begin to activate near –60 mV.     

Spike-timing precision and neuronal synchrony are enhanced by an interaction between synaptic inhibition and membrane oscillations in the amygdala

The basolateral complex of the amygdala (BLA) is a critical component of the neural circuit regulating fear learning. During fear learning and recall, the amygdala and other brain regions, including the hippocampus and prefrontal cortex, exhibit phase-locked oscillations in the high delta/low theta frequency band (～2-6 Hz) that have been shown to contribute to the learning process. Network oscillations are commonly generated by inhibitory synaptic input that coordinates action potentials in groups of neurons. In the rat BLA, principal neurons spontaneously receive synchronized, inhibitory input in the form of compound, rhythmic, inhibitory postsynaptic potentials (IPSPs), likely originating from burst-firing parvalbumin interneurons. Here we investigated the role of compound IPSPs in the rat and rhesus macaque BLA in regulating action potential synchrony and spike-timing precision. Furthermore, because principal neurons exhibit intrinsic oscillatory properties and resonance between 4 and 5 Hz, in the same frequency band observed during fear, we investigated whether compound IPSPs and intrinsic oscillations interact to promote rhythmic activity in the BLA at this frequency. Using whole-cell patch clamp in brain slices, we demonstrate that compound IPSPs, which occur spontaneously and are synchronized across principal neurons in both the rat and primate BLA, significantly improve spike-timing precision in BLA principal neurons for a window of ～300 ms following each IPSP. We also show that compound IPSPs coordinate the firing of pairs of BLA principal neurons, and significantly improve spike synchrony for a window of ～130 ms. Compound IPSPs enhance a 5 Hz calcium-dependent membrane potential oscillation (MPO) in these neurons, likely contributing to the improvement in spike-timing precision and synchronization of spiking. Activation of the cAMP-PKA signaling cascade enhanced the MPO, and inhibition of this cascade blocked the MPO. We discuss these results in the context of spike-timing dependent plasticity and modulation by neurotransmitters important for fear learning, such as dopamine.     

Intrinsic and synaptic properties of neurons in the vocal-control nucleus lMAN from in vitro slice preparations of juvenile and adult zebra finches

A common theme of diverse neural systems is that circuits that are important for initial acquisition of learning do not necessarily serve as a substrate for the long-term storage of that memory. The neural basis of vocal learning in songbirds provides an example of this phenomenon, since a circuit that is necessary for vocal production during initial stages of vocal development apparently plays no subsequent role in controlling learned vocalizations. This striking functional change suggests the possibility of marked physiological changes in synaptic transmission within this circuit. We therefore examined intrinsic and synaptic properties of neurons in the cortical nucleus lMAN (lateral magnocellular nucleus of the anterior neostriatum), which forms part of this developmentally regulated circuit, in an in vitro preparation of the zebra finch forebrain. Although both functional and morphological characteristics of these neurons change substantially during vocal development, we did not observe widespread, substantive changes in the electrophysiological characteristics of juvenile versus adult lMAN neurons examined in vitro. Overall, both the intrinsic properties and synaptic responses of lMAN neurons were similar in slices from juvenile birds (at ages when lesions of lMAN disrupt vocal production) and in slices from adult birds (when lMAN lesions have no effect on song production). However, one intrinsic property that did vary between juvenile and adult cells was spike duration, which was longer in juvenile cells, suggesting the potential for activation of second-messenger cascades and/or enhanced synaptic transmission onto target cells of lMAN neurons. The pattern of synaptic response observed in both juvenile and adult cells suggests that lMAN projection neurons receive direct excitatory afferent inputs, as well as disynaptic inhibitory inputs from interneurons within lMAN. Activation of inhibitory interneurons rapidly curtails the excitatory response seen in projection neurons. This inhibition was abolished by bicuculline, indicating that the inhibitory interneurons normally exert their postsynaptic response via GABA_A receptors on projection neurons. The inhibitory response could also be blocked by CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), suggesting that the activation of inhibitory interneurons within lMAN may be governed primarily by AMPA receptors. © 1998 John Wiley & Sons, Inc. J Neurobiol 37: 642–658, 1998     

Motor pattern switching in the heartbeat pattern generator of the medicinal leech: membrane properties and lack of synaptic interaction in switch interneurons

The motor program for heartbeat in the medicinal leech is produced by a central pattern generator that regularly switches between two alternative coordination states. A pair of switch heart interneurons reciprocally alternate between rhythmically active and inactive states to effect these switches. During spontaneous switches in the activity state of switch interneurons, there was no correlation between the duration of a particular activity state and beat period, indicating that the timing networks for the switch cycle and the beat cycle are relatively independent. Simultaneous recordings from two switch heart interneurons showed that a perturbation in the electrical activity of one does not influence switching of the other and that there is no synaptic interaction between them. Using voltage clamp, we characterized an L-like Ca²⁺ current (measured as Ba²⁺ currents), inactivating and non-inactivating K⁺ currents, a persistent Na⁺ current, and a hyperpolarization-activated inward current in switch interneurons. Dynamic clamp experiments show that “subtraction” of an artificial switch leak conductance (described previously by Gramoll et al. 1994) from a switch interneuron when it is in the inactive state causes it to display activity associated with the active state. We discuss how the switch leak conductance may interact with the intrinsic currents of switch interneurons to control their activity state. Accepted: 1 December 1998     

Generation of locomotion rhythms without inhibition in vertebrates: the search for pacemaker neurons

Locomotion rhythms are thought to be generated by neurons in the central-pattern-generator (CPG) circuit in the spinal cord. Synaptic connections in the CPG and pacemaker properties in certain CPG neurons, both may contribute to generation of the rhythms. In the half-center model proposed by Graham Brown a century ago, reciprocal inhibition plays a critical role. However, in all vertebrate preparations examined, rhythmic motor bursts can be induced when inhibition is blocked in the spinal cord. Without inhibition, neuronal pacemaker properties may become more important in generation of the rhythms. Pacemaker properties have been found in motoneurons and some premotor interneurons in different vertebrates and they can be dependent on N-Methyl-d-aspartate (NMDA) receptors (NMDAR) or rely on other ionic currents like persistent inward currents. In the swimming circuit of the hatchling Xenopus tadpole, there is substantial evidence that emergent network properties can give rise to swimming rhythms. During fictive swimming, excitatory interneurons (dINs) in the caudal hindbrain fire earliest on each swimming cycle and their spikes drive the firing of other CPG neurons. Regenerative dIN firing itself relies on reciprocal inhibition and background excitation. We now find that the activation of NMDARs can change dINs from firing singly at rest to current injection to firing repetitively at swimming frequencies. When action potentials are blocked, some intrinsic membrane potential oscillations at about 10 Hz are revealed, which may underlie repetitive dIN firing during NMDAR activation. In confirmation of this, dIN repetitive firing persists in NMDA when synaptic transmission is blocked by Cd(2+). When inhibition is blocked, only dINs and motoneurons are functional in the spinal circuit. We propose that the conditional intrinsic NMDAR-dependent pacemaker firing of dINs can drive the production of swimming-like rhythms without the participation of inhibitory neurotransmission.     

Inhibitory effects of reticulospinal fibers of the lateral funiculus on neurons of thoracic spinal reflex pathways

Experiments on anesthetized cats with partial transection of the spinal cord showed that reticulo-spinal fibers in the ventral part of the lateral funiculus participate in the inhibition of polysynaptic reflexes evoked by stimulation of the ipsi- and contralateral reticular formation. The reticulo-fugal wave in the ventrolateral funiculus evoked comparatively short (up to 70 msec) IPSPs in some motoneurons of the internal intercostal nerve investigated and at the same time evoked prolonged (up to 500 msec) inhibition of IPSPs caused by activation of high-threshold segmental afferents. This wave also led to the appearance of IPSPs in 14 of 91 (15.5 %) thoracic spinal interneurons studied. The duration of these IPSPs did not exceed 100 msec; meanwhile, segment excitatory responses of 21 of 43 interneurons remained partly suppressed for 120–500 msec. It is concluded that the inhibitory action of the lateral reticulo-spinal system on segmental reflexes is due to several synaptic mechanisms, some of them unconnected with hyperpolarization of spinal neurons. The possible types of mechanisms of this inhibition are discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 10, No. 2, pp. 162–172, March–April, 1978.     

Modeling a Neural Oscillator that Paces Heartbeat in the Medicinal Leech

SYNOPSIS. Heartbeat in the medicinal leech is paced by a neuraloscillator comprising two elemental oscillators whose activityis coordinated intersegmental coordinating fibers. The elementaloscillators each consist of a bilateral pair of heart interneuronslinked by reciprocal inhibitory synapses. The activity cycleof each elemental oscillator consists of alternating burstsof action potentials (plateau/burst phase) and periods inhibition(inactive phase). Oscillation ensues in the reciprocally inhibitorypairs because each neuron is able to escape from the inhibitionits contralateral partner and thus move on to the plateau/burstphase. We have identified and described membrane currents thatcontribute to oscillation and studied graded synaptic transmissionbetween the neurons, using discontinuous current clamp and switchingsingle electrode voltage clamp techniques. A hyperpolarization-activatedinward current, Ih, plays a major role in escape from inhibition,and Ca²⁺ currents produce plateau potentials that support burstformation and mediate graded synaptic transmission. To consolidate our knowledge and guide future research, we haveconstructed a first generation computer model of a neural oscillatorbased on reciprocal inhibition, using Hodgkin-Huxley equationsand a synaptic transfer model, derived from our biophysicalstudies, with Nodus software (De Schutter, 1989). This modelhas confirmed an important role for I_h in sustaining oscillationand has implicated a similarly important role for outward currents(particularly I_A), which remain to be studied. Neural oscillatorsbased on reciprocal inhibition appear to be ubiquitous, andour studies, biophysical and computational, provide insightsinto how they may operate.     

Modeling the leech heartbeat elemental oscillator II. Exploring the parameter space

In the previous paper, we described a model of the elemental heartbeat oscillator in the leech. Here, the parameters of our model are explored around the baseline canonical model. The maximal conductances of the currents and the reversal potential of the leak current are varied to reveal the effects of individual currents and the interaction between synaptic and intrinsic currents in the model. The model produces two distinct modes of oscillation as the parameters are varied, S-mode and G-mode. These two modes are defined, their origin is identified, and the parameter space is mapped into S-mode and G-mode oscillation and no oscillation. Finally, we will make predictions for how the period can be modulated in heart interneurons.     

EPSP amplification and the precision of spike timing in hippocampal neurons

The temporal precision with which EPSPs initiate action potentials in postsynaptic cells determines how activity spreads in neuronal networks. We found that small EPSPs evoked from just subthreshold potentials initiated firing with short latencies in most CA1 hippocampal inhibitory cells, while action potential timing in pyramidal cells was more variable due to plateau potentials that amplified and prolonged EPSPs. Action potential timing apparently depends on the balance of subthreshold intrinsic currents. In interneurons, outward currents dominate responses to somatically injected EPSP waveforms, while inward currents are larger than outward currents close to threshold in pyramidal cells. Suppressing outward potassium currents increases the variability in latency of synaptically induced firing in interneurons. These differences in precision of EPSP-spike coupling in inhibitory and pyramidal cells will enhance inhibitory control of the spread of excitation in the hippocampus.     

Two Fast Transient Current Components during Voltage Clamp on Snail Neurons

Voltage clamp currents from medium sized ganglion cells of Helix pomatia have a fast transient outward current component in addition to the usually observed inward and outward currents. This component is inactivated at normal resting potential. The current, which is carried by K+ ions, may surpass leakage currents by a factor of 100 after inactivation has been removed by hyperpolarizing conditioning pulses. Its kinetics are similar to those of the inward current, except that it has a longer time constant of inactivation. It has a threshold close to resting potential. This additional component is also present in giant cells, where however, it is less prominent. Pacemaker activity is controlled by this current. It was found that inward currents have a slow inactivating process in addition to a fast, Hodgkin-Huxley type inactivation. The time constants of the slow process are similar to those of slow outward current inactivation.     

Changes in inhibitory CA1 network in dual pathology model of epilepsy

The combination of two precipitating factors appears to be more and more recognized in patients with temporal lobe epilepsy. Using a two-hit rat model, with a neonatal freeze lesion mimicking a focal cortical malformation combined with hyperthermia-induced seizures mimicking febrile seizures, we have previously reported an increase of inhibition in CA1 pyramidal cells at P20. Here, we investigated the changes affecting excitatory and inhibitory drive onto CA1 interneurons to better define the changes in CA1 inhibitory networks and their paradoxical role in epileptogenesis, using electrophysiological recordings in CA1 hippocampus from rat pups (16–20 d old). We investigated interneurons in CA1 hippocampal area located in stratum oriens (Or) and at the border of strata lacunosum and moleculare (L-M). Our results revealed an increase of the excitatory drive to both types of interneurons with no change in the inhibitory drive. The mechanisms underlying the increase of excitatory synaptic currents (EPSCs) in both types of interneurons are different. In Or interneurons, the amplitude of spontaneous and miniature EPSCs increased, while their frequency was not affected suggesting changes at the post-synaptic level. In L-M interneurons, the frequency of spontaneous EPSCs increases, but the amplitude is not affected. Analyses of miniature EPSCs showed no changes in both their frequency and amplitude. We concluded that L-M interneurons increase in excitatory drive is due to a change in Shaffer collateral axon excitability. The changes described here in CA1 inhibitory network may actually contribute to the epileptogenicity observed in this dual pathology model by increasing pyramidal cell synchronization.     

Action Potential Modulation in CA1 Pyramidal Neuron Axons Facilitates OLM Interneuron Activation in Recurrent Inhibitory Microcircuits of Rat Hippocampus

Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outside-out patch recordings from CA1 pyramidal neuron axons revealed a high density of α-dendrotoxin (α-DTX)-sensitive, inactivating K⁺ channels, suggesting that K⁺ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron–O-LM interneuron excitatory postsynaptic currents (EPSCs) showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K⁺ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron–interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.     

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.     

Neuronal and synaptic mechanisms of cortical inhibition

The latent periods, amplitude, and duration of IPSPs arising in neurons in different parts of the cat cortex in response to afferent stimuli, stimulation of thalamocortical fibers, and intracortical microstimulation are described. The duration of IPSPs evoked in cortical neurons in response to single afferent stimuli varied from 20 to 250 msec (most common frequency 30–60 msec). During intracortical microstimulation of the auditory cortex, IPSPs with a duration of 5–10 msec also appeared. Barbiturates and chloralose increased the duration of the IPSPs to 300–500 msec. The latent period of 73% of IPSPs arising in auditory cortical neurons in response to stimulation of thalamocortical fibers was 1.2 msec longer than the latent period of monosynaptic EPSPs evoked in the same way. It is concluded from these data that inhibition arising in most neurons of cortical projection areas as a result of the arrival of corresponding afferent impulsation is direct afferent inhibition involving the participation of cortical inhibitory interneurons. A mechanism of recurrent inhibition takes part in the development of inhibition in a certain proportion of neurons. IPSPs arise monosynaptically in 2% of cells. A study of responses of cortical neurons to intracortical microstimulation showed that synaptic delay of IPSPs in these cells is 0.3–0.4 msec. The length of axons of inhibitory neurons in layer IV of the auditory cortex reaches 1.5 mm. The velocity of spread of excitation along these axons is 1.6–2.8 msec (mean 2.2 msec).A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 16, No. 3, pp. 394–403, May–June, 1984.     

Tonic inhibition in spinal ventral horn interneurons mediated by α5 subunit-containing GABA(A) receptors

GABA_A receptors mediate synaptic and tonic inhibition in many neurons of the central nervous system. These receptors can be constructed from a range of different subunits deriving from seven identified families. Among these subunits, α₅ has been shown to mediate GABAergic tonic inhibitory currents in neurons from supraspinal nuclei. Likewise, immunohistochemical and in situ hybridization studies have shown the presence of the α₅ subunit in spinal cord neurons, though almost nothing is known about its function. In the present report, using slices of the adult turtle spinal cord as a model system we have recorded a tonic inhibitory current in ventral horn interneurons (VHIs) and determined the functional contribution of the α₅ subunit-containing GABA_A receptors to this current. Patch clamp studies show that the GABAergic tonic inhibitory current in VHIs is not affected by the application of antagonists of the α_4/6 subunit-containing GABA_A receptors, but is sensitive to L-655708, an antagonist of the GABA_A receptors containing α₅ subunits. Last, by using RT-PCR and immunohistochemistry we confirmed the expression of the α₅ subunit in the turtle spinal cord. Together, these results suggest that GABA_A receptors containing the α₅ subunit mediate the tonic inhibitory currents observed in VHIs.     

Dynamic model of neuronal response in the rat hippocampus

A linear lumped model was proposed for the hippocampal CA 1 region of anesthetized rats using differential equations of time-independent coefficients, the afferent and efferent fibers of the alveus as inputs and the averaged evoked potentials (AEPs) and poststimulus time histograms as outputs. The alvear tract, a major efferent path, was proposed to activate interneurons monosynaptically while the anterior alveus activated orthodromically pyramidal cells which then excited the interneurons. The interneurons then inhibited pyramidal cells. The observable field outputs were the excitatory postsynaptic potentials (EPSPs) of interneurons and the inhibitory postsynaptic potentials (IPSPs) of pyramidal cells. Positive neurophysiological feedbacks were proposed among interneurons and among pyramidal cells in order to account for the prolonged time courses of the interneuronal EPSPs and the pyramidal cell IPSPs. The parameters of the model were optimized by a nonlinear regression program which minimized the sum of squared deviations between the model-generated and actual AEPs. The parameters included the temporal dispersion of the input tract (about 3 ms) and the membrane time constant of interneuronal and pyramidal cell populations (4.8 ms). In anesthetized rats, positive feedback gain coefficients were 0.07 among interneurons and 0.85 among pyramidal cells. After a compound spike (I), two postsynaptic AEP components (II and III) of different time courses were detectable at all depths within CA 1 except at the turnover for each component. The hypothesis that the AEP component II was generated by interneurons was tested and confirmed. The quantitative model constitutes a concise construct of the functional organization of the hippocampal CA 1 region, which suggests further theoretical extensions and experimentation.     

Study of role of inhibitory interneurons in mechanisms of regulation of sensory synapses formed by thalamic and cortical inputs on pyramidal cells of the dorsolateral amygdala nucleus

The work deals with study of role of inhibitory interneurons in the process of regulation of sensory currents converging on soma of pyramidal cells of the dorsolateral amygdala nucleus as well as of role of these interneurons in mechanism of regulation of plasticity of amygdala synapses. It has been shown that the part of the spontaneous inhibitory postsynaptic currents recorded on the dorsolateral amygdala pyramidal cells is relatively high and amounts to about a half of the total amount of the recorded events. Analysis of the evoked postsynaptic responses has shown the interneurons to regulate activity and duration of these responses due to the postsynaptic membrane hyperpolarization as a result of activation of GABA_A-receptors. Also studied was role of interneurons in providing mechanisms of the long-term potentiation of the synaptic responses evoked by stimulation of cortical and thalamic inputs. Block of effect of interneurons with help of picrotoxin has been shown to lead to an increase of evoked potentiation of synaptic responses.