Level Of Tonic Inhibition Research Articles

Study of GABAergic extra-synaptic tonic inhibition in single neurons and neural populations by traversing neural scales: application to propofol-induced anaesthesia.

Anaesthetic agents are known to affect extra-synaptic GABAergic receptors, which induce tonic inhibitory currents. Since these receptors are very sensitive to small concentrations of agents, they are supposed to play an important role in the underlying neural mechanism of general anaesthesia. Moreover anaesthetic agents modulate the encephalographic activity (EEG) of subjects and hence show an effect on neural populations. To understand better the tonic inhibition effect in single neurons on neural populations and hence how it affects the EEG, the work considers single neurons and neural populations in a steady-state and studies numerically and analytically the modulation of their firing rate and nonlinear gain with respect to different levels of tonic inhibition. We consider populations of both type-I (Leaky Integrate-and-Fire model) and type-II (Morris-Lecar model) neurons. To bridge the single neuron description to the population description analytically, a recently proposed statistical approach is employed which allows to derive new analytical expressions for the population firing rate for type-I neurons. In addition, the work shows the derivation of a novel transfer function for type-I neurons as considered in neural mass models and studies briefly the interaction of synaptic and extra-synaptic inhibition. We reveal a strong subtractive and divisive effect of tonic inhibition in type-I neurons, i.e. a shift of the firing rate to higher excitation levels accompanied by a change of the nonlinear gain. Tonic inhibition shortens the excitation window of type-II neurons and their populations while maintaining the nonlinear gain. The gained results are interpreted in the context of recent experimental findings under propofol-induced anaesthesia.

GABAA receptor modulation by neurosteroids in models of temporal lobe epilepsies

Epilepsies consist of a spectrum of neurologic disorders typically characterized by unpredictable and dysfunctional network behaviors in the central nervous system (CNS), which lead to discrete episodes of large bouts of uncontrolled neuronal synchrony that interfere with the normal functioning of the brain. Temporal lobe epilepsy (TLE) is accompanied by changes in interneuronal innervation and modifications in different γ-aminobutyric acid (GABA)(A) receptor subunits. Hormones play an important role in modulating the overall excitability of neurons, and at the same time hormonal pathways are frequently modified during epilepsy. This review focuses on TLE-correlated modifications of GABAergic transmission, and in particular on the implications of some of our own findings related to GABA(A) Rs containing the δ subunits (δ-GABA(A) Rs). These are extra- or perisynaptic GABA(A) Rs that mediate tonic inhibition, a major component of the inhibitory mechanism in the brain. The most potent endogenous modulators of δ-GABA(A) Rs are neurosteroids, which act as positive allosteric modulators. Plasticity of δ-GABA(A) Rs during TLE consists of down-regulation of the subunit in the dentate gyrus granule cells (DGGCs), while being up-regulated in interneurons. Surprisingly, the level of tonic inhibition in DGGCs remains unchanged, consistent with the idea that it becomes mediated by GABA(A) Rs containing other subunits. In parallel, tonic inhibition in a TLE model ceases to be sensitive to neurosteroid potentiation. In contrast, as predicted by the anatomic plasticity, interneuronal tonic current is increased, and remains sensitive to neurosteroids. These findings have important pharmacologic implications. Where neurosteroids normally have sedative and anticonvulsant effects, bimodal and cell-type specific modulations in their natural targets might weaken the inhibitory control on the dentate gate, under circumstances of altered neurosteroids levels (stress, ovarian cycle, or the postpartum period).

General anaesthetics induce tonic inhibition and modulate the gain of neural populations : a modeling study

Anaesthetic agents are known to affect extra-synaptic GABAergic receptors[1], which induce tonic inhibitory currents. Since these receptors are very sensitive to small concentrations of agents, they are supposed to play an important role in the underlying neural mechanism of general anaesthesia. Moreover anaesthetic agents modulate the encephalographic activity (EEG) of patients and hence show an effect on neural populations. To understand better the tonic inhibition effect in single neurons on neural populations modulating the EEG, the work considers a neural population in a steady-state and studies numerically and analytically the modulation of its population firing rate and the nonlinear gain with respect to different levels of tonic inhibition. We consider populations of both type-I and type-II neurons. The populations under study are heterogeneous involving distributions of firing thresholds and inhibitory conductances. The tonic inhibition introduces shunting action.

Insulin Reduces Neuronal Excitability by Turning on GABAA Channels that Generate Tonic Current

Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (γ-aminobutyric acid) decreases neuronal excitability by activating GABAA channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocamal slices that insulin (1 nM) “turns on” new extrasynaptic GABAA channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC50) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABAA antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists. The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and disease.

Theta-modulated feedforward network generates rate and phase coded firing in the entorhino-hippocampal system.

Principal cells of the hippocampus and of its only cortical input region, the entorhinal cortex exhibit place specific activity in the freely moving rat. While entorhinal cells have widely tuned place fields, hippocampal place fields are more localized and determine not only the rate but also the timing of place cell spikes. Several models have successfully attempted to explain this fine tuning making use of intrahippocampal attractor network dynamics provided by the recurrent collaterals of hippocampal area CA3. Recent experimental evidence shows that CA1 place cells preserve their tuning curves even in the absence of input from CA3. We propose a model in which entorhinal and hippocampal pyramidal cell populations are only connected via feedforward connections. Synaptic transmission in our sytem is gated by a class of interneurons inhibiting specifically the entorhino-hippocampal pathway. Theta rhythm modulates the activity of each component. Our results show that rhythmic shunting inhibition endows entorhinal cells with a novel type of temporal code conveyed by the phase jitter of individual spikes. This converts coarsely tuned place-specific activity in the entorhinal cortex to velocity-dependent postsynaptic excitation and, thus, provides hippocampal place cells with an input that has recently been proposed to account for their rate and phase coded firing. Hippocampal place fields are generated through this mechanism and also shown to be robust against variations in the level of tonic inhibition.

Prenatal Protein Malnutrition Results in Increased Frequency of Miniature Inhibitory Postsynaptic Currents in Rat CA3 Interneurons

Electrophysiological studies have revealed an increase in the level of tonic inhibition in the hippocampus following prenatal protein malnutrition in rats. In the present study, whole cell patch clamp recordings of bipolar interneurons in the stratum radiatum of the CA3 subfield were used to determine whether this increase in inhibition can be accounted for by a change in the electrophysiological properties of GABAergic interneurons. Hippocampal slices were prepared from juvenile rats whose dams were fed either a normal (25% casein) or low (6% casein) protein diet throughout pregnancy. Intrinsic membrane and action potential properties were unaltered by the prenatal nutritional insult. In most respects the characteristics of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) and the modulation of such currents by the benzodiazepine agonist zolpidem were also similar in cells from the two nutritional groups. While the frequency of spontaneous inhibitory currents was unaltered, miniature (Tetrodotoxin resistant) inhibitory currents occurred at a significantly increased frequency in interneurons from prenatally protein malnourished rats. Thus, while the basic membrane properties of interneurons are preserved, there is a significant increase in the probability of GABA release from interneurons following prenatal protein malnutrition.

Effects of locus coeruleus stimulation on the responses of SI neurons of the rat to controlled natural and electrical stimulation of the skin.

1. The effects of microstimulation of the locus coeruleus (LC) region on the spontaneous discharge and the response of SI neurons to natural and electrical stimulation of the skin have been investigated in 26 urethane anesthetized Sprague-Dawley rats. In particular, one or two air puffs, 5-10 msec in duration, 1-2 psi, usually separated by an interval of 40 msec, were applied on the hairy skin of the wrist or the forepaw at the presentation rate of 1/sec. For units unresponsive to air puffs, similar presentation of low intensity electrical stimuli (0.2-5.0 V, 0.2-0.4 msec pulses) were applied through two needles inserted on the most effective area of the skin. Both natural and electrical stimulations of the skin were applied under control conditions, as well as 50 msec after a 250 msec train of 0.3 msec pulses at 40 Hz. 20-30 microA applied stereotaxically to the LC complex through a tungsten microelectrode. 2. Not all cortical units exhibited spontaneous discharge. Most of the units, however, which were spontaneously active, were inhibited by electrical stimulation of the LC complex, while the remaining ones were excited. The sites of stimulation, which included either the LC proper or the locus subcoeruleus, were identified following both anatomical and physiological criteria. 3. SI neurons recorded at sites between 400 and 950 microns below the surface of the cortex, thus being most likely granule cells of layers III and IV, responded to cutaneous stimuli with spikes which occurred with a latency of 20-30 msec in response to single air puffs and a latency of 15-20 msec in response to single electrical pulses to the skin. In both instances the response to the second stimulus applied at the interstimulus interval of 40 msec was markedly reduced or abolished due to postexcitatory inhibition following the response to the first stimulus (in-field inhibition). In contrast, units particularly located at or below 1000 microns from the cortical surface, which were of very large size probably corresponding to large layer V pyramidal cells, were often difficult to activate with air puffs applied at the centre of the receptive field (RF) and were submitted to electrical stimulation of the skin. 4. Among the 59 isolated SI units tested either to air puffs (45 neurons) or to electrical skin stimulation (14 neurons), 15 units (i.e., 25.4%) were facilitated, while 12 units (i.e., 20.3%) were inhibited following stimulation of the LC complex. 5. A marked feature of the facilitatory effects which usually involved the predominant response to the first air puff, but also the smaller response to the second puff, was that the increase in the number of spikes per stimulus was accompanied by a temporal focusing of the responses characterized by a clear tightening of the latency and narrowing of the peak of activity, which was often accompanied by some level of tonic inhibition of the background discharge. Thus, LC stimulation increased the signal-to-noise ratio of SI neuronal responses to skin stimulation. When inhibitory effects were induced by LC stimulation, they clearly affected the unit response to the first air puff, which was severely depressed. However, the response to the second puff could be facilitated, suggesting that LC stimulation might have produced inhibition of those inhibitory interneurons responsible for the postexcitatory inhibition of the units under examination. Evidence for spatial focusing of the response was not easily documented. In some units, however, LC stimulation produced either facilitation of the responses to puffs at the receptive field center and inhibition of the responses to puffs at the edge at the receptive field or vice versa. 6. Since the LC complex contains in the rat a predominant population of noradrenergic neurons, it is likely that the effects described above were mainly due to activation of these noradrenergic neurons. 7. (ABSTRACT TRUNCATED)

Decrease in inhibition in dentate granule cells from patients with medial temporal lobe epilepsy.

Alterations in synaptic inhibition are associated with epileptiform activity in several acute animal models; however, it is not clear if there are changes in inhibition in chronically epileptic tissue. We have used intracellular recordings from granule cells of patients with temporal lobe epilepsy to determine whether synaptic inhibition is compromised. Two groups of patients with medial temporal lobe epilepsy were used, those with medial temporal lobe sclerosis (MTLE), and those with extrahippocampal masses (MaTLE) where the cell loss and synaptic reorganization that characterize MTLE are not seen. Although the level of tonic inhibition at the somata was not significantly different in the two patient groups, there was a reduction in the conductance of polysynaptic perforant path-evoked fast and slow inhibitory postsynaptic potentials (IPSPs) (53% and 66%, respectively). We found that there was a comparable decrease in the monosynaptic IPSP conductances examined in the presence of glutamatergic antagonists as that seen for the polysynaptically evoked IPSPs. These data suggest that the decrease in inhibition seen in normal artificial cerebrospinal fluid in MTLE granule cells cannot be solely explained by a decrease in excitatory input onto inhibitory interneurons and may reflect changes at the interneuron-granule cells synapse or in the number of specific inhibitory interneurons.

Tonic Synaptic Inhibition Modulates Neuronal Output Pattern and Spatiotemporal Synaptic Integration

Irregular firing patterns are observed in most central neurons in vivo, but their origin is controversial. Here, we show that two types of inhibitory neurons in the cerebellar cortex fire spontaneously and regularly in the absence of synaptic input but generate an irregular firing pattern in the presence of tonic synaptic inhibition. Paired recordings between synaptically connected neurons revealed that single action potentials in inhibitory interneurons cause highly variable delays in action potential firing in their postsynaptic cells. Activity in single and multiple inhibitory interneurons also significantly reduces postsynaptic membrane time constant and input resistance. These findings suggest that the time window for synaptic integration is a dynamic variable modulated by the level of tonic inhibition, and that rate coding and temporal coding strategies may be used in parallel in the same cell type.

Delayed sexual maturation induced by daily melatonin administration eliminates the LH response to naloxone despite normal responsiveness to GnRH in juvenile male rats.

Daily administration of melatonin (MT) markedly delays sexual maturation in the male Wistar rat. In this study, we have evaluated pituitary responsiveness to GnRH and the level of tonic inhibition by endogenous opioids in normal juvenile male rats and in rats with delayed sexual development induced by daily afternoon MT injection (100 micrograms, s.c.) starting at 20 days of life. Plasma LH responses to repetitive intravenous GnRH administration (100 ng/100 g body weight), or to different doses of GnRH administered subcutaneously (5-100 ng/100 g body weight) were normal in MT-treated rats both at 30 and 40 days of life despite significantly lower number of pituitary GnRH receptors and decreased pituitary gonadotropin content. One naloxone (NAL) injection (2.5-5.0 mg/kg, s.c.) produced a significant increase of plasma LH in normal 40- and 55-day-old rats, which was not seen in MT-treated rats of the same age. In contrast, no increase of plasma LH was seen in 30-day-old control rats nor in MT-treated rats at this age. Pretreatment with morphine sulfate (10 mg/kg, s.c.), or with the potent Met-enkephalin analog FK 33-824 (1.0 mg/kg, s.c.) prevented the NAL-induced rise of plasma LH in control rats at day 40 of life. In all instances, plasma PRL levels were decreased after NAL both in untreated and in MT-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)