Active dendritic conductances dynamically regulate GABA release from thalamic interneurons

Inhibitory interneurons in the dorsal lateral geniculate nucleus (dLGN) process visual information by precisely controlling spike timing and by refining the receptive fields of thalamocortical (TC) neurons. Previous studies indicate that dLGN interneurons inhibit TC neurons by releasing GABA from both axons and dendrites. However, the mechanisms controlling GABA release are poorly understood. Here, using simultaneous whole-cell recordings from interneurons and TC neurons and two-photon calcium imaging, we find that synchronous activation of multiple retinal ganglion cells (RGCs) triggers sodium spikes that propagate throughout interneuron axons and dendrites, and calcium spikes that invade dendrites but not axons. These distinct modes of interneuron firing can trigger both a rapid and a sustained component of inhibition onto TC neurons. Our studies suggest that active conductances make LGN interneurons flexible circuit-elements that can shift their spatial and temporal properties of GABA release in response to coincident activation of functionally related subsets of RGCs.     

Desynchronization of Neocortical Networks by Asynchronous Release of GABA at Autaptic and Synaptic Contacts from Fast-Spiking Interneurons

Networks of specific inhibitory interneurons regulate principal cell firing in several forms of neocortical activity. Fast-spiking (FS) interneurons are potently self-inhibited by GABAergic autaptic transmission, allowing them to precisely control their own firing dynamics and timing. Here we show that in FS interneurons, high-frequency trains of action potentials can generate a delayed and prolonged GABAergic self-inhibition due to sustained asynchronous release at FS-cell autapses. Asynchronous release of GABA is simultaneously recorded in connected pyramidal (P) neurons. Asynchronous and synchronous autaptic release show differential presynaptic Ca²⁺ sensitivity, suggesting that they rely on different Ca²⁺ sensors and/or involve distinct pools of vesicles. In addition, asynchronous release is modulated by the endogenous Ca²⁺ buffer parvalbumin. Functionally, asynchronous release decreases FS-cell spike reliability and reduces the ability of P neurons to integrate incoming stimuli into precise firing. Since each FS cell contacts many P neurons, asynchronous release from a single interneuron may desynchronize a large portion of the local network and disrupt cortical information processing.     

Retrograde GABA signaling adjusts sound localization by balancing excitation and inhibition in the brainstem

Central processing of acoustic cues is critically dependent on the balance between excitation and inhibition. This balance is particularly important for auditory neurons in the lateral superior olive, because these compare excitatory inputs from one ear and inhibitory inputs from the other ear to compute sound source location. By applying GABA(B) receptor antagonists during sound stimulation in vivo, it was revealed that these neurons adjust their binaural sensitivity through GABA(B) receptors. Using an in vitro approach, we then demonstrate that these neurons release GABA during spiking activity. Consequently, GABA differentially regulates transmitter release from the excitatory and inhibitory terminals via feedback to presynaptic GABA(B) receptors. Modulation of the synaptic input strength, by putative retrograde release of neurotransmitter, may enable these auditory neurons to rapidly adjust the balance between excitation and inhibition, and thus their binaural sensitivity, which could play an important role as an adaptation to various listening situations.     

The influence of neuromodulators on the synaptic plasticity in dopaminergic structures of the midbrain (hypothetical mechanism)

A mechanism underlying the effects of neuromodulators on long-term changes in the efficacy of excitatory and inhibitory inputs to dopaminergic and inhibitory cells of the substantia nigra and ventral tegmental area is suggested. According to this mechanism, activation of Gi/0 protein-coupled dopamine D2 autoreceptors and opioid kappa (mu) receptors on dopaminergic (inhibitory) cells promotes the LTD of excitatory inputs to these cells and decrease in their activity. Activation of Gq/11 protein-coupled alpha1 adrenoreceptors, muscarinic M1, neurokinin NK3 (alpha1, M3, NK1, serotonin 5-HT2) receptors on dopaminergic (inhibitory) cells as well as activation of Gs protein-coupled D1 receptors on inhibitory cells promotes the LTP of excitatory inputs to these cells and increase in their activity. Augmenting (lowering) GABA release can be provided by activation of presynaptic D1 and M3 receptors (mu, 5-HT1, and adenosine A1) receptors. Increase (decrease) in GABA concentration due to modulation of inhibitory cell activity and/or GABA release will promote the induction of LTD (LTP) of excitatory inputs to target dopamine cells. The model agree with known experimental data describing the involvement of neuromodulators in modification of dopamine cell activity and dopamine release. The suggested model can be useful in understanding the operation of neuronal networks, which include the basal ganglia.     

Multiple clusters of release sites formed by individual thalamic afferents onto cortical interneurons ensure reliable transmission

Thalamic afferents supply the cortex with sensory information by contacting both excitatory neurons and inhibitory interneurons. Interestingly, thalamic contacts with interneurons constitute such a powerful synapse that even one afferent can fire interneurons, thereby driving feedforward inhibition. However, the spatial representation of this potent synapse on interneuron dendrites is poorly understood. Using Ca imaging and electron microscopy we show that an individual thalamic afferent forms multiple contacts with the interneuronal proximal dendritic arbor, preferentially near branch points. More contacts are correlated with larger amplitude synaptic responses. Each contact, consisting of a single bouton, can release up to seven vesicles simultaneously, resulting in graded and reliable Ca transients. Computational modeling indicates that the release of multiple vesicles at each contact minimally reduces the efficiency of the thalamic afferent in exciting the interneuron. This strategy preserves the spatial representation of thalamocortical inputs across the dendritic arbor over a wide range of release conditions.     

A possible mechanism of the influence of neuromodulators and modifiable inhibition on long-term potentiation and long-term depression of excitatory inputs to main hippocampal neurons

A hypothetic mechanism explaining the influence of various neuromodulators and modifiable disynaptic inhibition on the long-term potentiation and depression (LTP and LTD) of excitatory inputs to granule and pyramidal hippocampal cells is proposed. According to this mechanism, facilitation of the LTD/LTP of excitatory inputs to an inhibitory interneuron caused by the action of a neuromodulator on a receptor bound with Gi/0/(Gs or Gq/11) protein can reduce/augment the GABA release, weaken/intensify the target cell inhibition, and promote the induction of the LTP/LTD of excitatory inputs to this cell. In the absence of the inhibition, the same neuromodulator would promote the LTD/LTP induction in the target cell by activating the same receptor types. The resulting effect of a neuromodulator on a target cell depends on the ratio between the "strengths" of its excitatory and inhibitory inputs, on the presence of receptors of the same or different types at the interneuron and the target cell, and on the neuromodulator concentration due to its different affinity for receptors, interaction with which provide its influence on postsynaptic processes in opposite directions. The consequences of suggested mechanism are in agreement with the known experimental data.     

Local interneurons and information processing in the olfactory glomeruli of the moth Manduca sexta

Intracellular recordings were made from the major neurites of local interneurons in the moth antennal lobe. Antennal nerve stimulation evoked 3 patterns of postsynaptic activity: (i) a short-latency compound excitatory postsynaptic potential that, based on electrical stimulation of the antennal nerve and stimulation of the antenna with odors, represents a monosynaptic input from olfactory afferent axons (71 out of 86 neurons), (ii) a delayed activation of firing in response to both electrical- and odor-driven input (11 neurons), and (iii) a delayed membrane hyperpolarization in response to antennal nerve input (4 neurons).Simultaneous intracellular recordings from a local interneuron with short-latency responses and a projection (output) neuron revealed unidirectional synaptic interactions between these two cell types. In 20% of the 30 pairs studied, spontaneous and current-induced spiking activity in a local interneuron correlated with hyperpolarization and suppression of firing in a projection neuron. No evidence for recurrent or feedback inhibition of projection neurons was found. Furthermore, suppression of firing in an inhibitory local interneuron led to an increase in firing in the normally quiescent projection neuron, suggesting that a disinhibitory pathway may mediate excitation in projection neurons. This is the first direct evidence of an inhibitory role for local interneurons in olfactory information processing in insects. Through different types of multisynaptic interactions with projection neurons, local interneurons help to generate and shape the output from olfactory glomeruli in the antennal lobe.Abbreviations AL antennal lobe - EPSP excitatory postsynaptic potential - GABA -aminobutyric acid - IPSP inhibitory postsynaptic potential - LN local interneuron - MGC macroglomerular complex - OB olfactory bulb - PN projection neuron - TES N-tris[hydroxymethyl]methyl-2-aminoethane-sulfonic acid     

Enhancement of asynchronous release from fast-spiking interneuron in human and rat epileptic neocortex

Down-regulation of GABAergic inhibition may result in the generation of epileptiform activities. Besides spike-triggered synchronous GABA release, changes in asynchronous release (AR) following high-frequency discharges may further regulate epileptiform activities. In brain slices obtained from surgically removed human neocortical tissues of patients with intractable epilepsy and brain tumor, we found that AR occurred at GABAergic output synapses of fast-spiking (FS) neurons and its strength depended on the type of connections, with FS autapses showing the strongest AR. In addition, we found that AR depended on residual Ca²⁺ at presynaptic terminals but was independent of postsynaptic firing. Furthermore, AR at FS autapses was markedly elevated in human epileptic tissue as compared to non-epileptic tissue. In a rat model of epilepsy, we found similar elevation of AR at both FS autapses and synapses onto excitatory neurons. Further experiments and analysis showed that AR elevation in epileptic tissue may result from an increase in action potential amplitude in the FS neurons and elevation of residual Ca²⁺ concentration. Together, these results revealed that GABAergic AR occurred at both human and rat neocortex, and its elevation in epileptic tissue may contribute to the regulation of epileptiform activities.     

The Role of Steroid Modulation of Amino Acid Transmitters in the Regulation of Female Reproduction

SYNOPSIS. The amino acid transmitters can be placed in two generalcategories, excitatory and inhibitory. This discussion focuseson the role of the inhibitory transmitter GAB A and the excitatoryamino acids aspartate and glutamate in the control of gonadotropinsecretion and reproductive behavior. GABAergic neurotransmissionin the preoptic area inhibits gonadotropin secretion via directsynaptic contact with LHRH neurons and possibly through presynapticinhibition of noradrenergic fibers that stimulate LH release.In the arcuate-median eminence, GABA acting at GABAA receptorsincreases gonadotropin release by inhibiting a currently unidentifiedinhibitory interneuron. In regard to reproductive behavior,GABA acting in the preoptic area inhibits female sexual receptivitywhereas GABA in the mediobasal hypothalamus and the midbraincentral gray facilitates this behavior. The effects of GABAon reproductive behavior do not appear to be secondary to actionson defensive or locomotor behavior. Gonadal steroids modulateactivity at the GABAA receptor in a highly complex manner andthese effects may be involved in the role GABA plays in controllinggonadotropin secretions as well as behavior. The excitatory amino acids also affect gonadotropin secretion,exerting a stimulatory effect both in the preoptic area andat the level of the median eminence. When a specific antagonistfor one of the excitatory amino acid receptors is infused intothe preoptic area or when an excitatory amino acid receptoragonist is infused into the mediobasal hypothalamus, femalesexual behavior is inhibited. There have only been limited reportsof steroid modulation of excitatory amino acid neurotransmission.     

GABA spillover activates postsynaptic GABA(B) receptors to control rhythmic hippocampal activity

In the hippocampus, interneurons provide synaptic inhibition via the transmitter GABA, which can activate GABA(A) and GABA(B) receptors (GABA(A)Rs and GABA(B)Rs). Generally, however, GABA released by a single interneuron activates only GABA(A)Rs on its targets, despite the abundance of GABA(B)RS. Here, I show that during hippocampal rhythmic activity, simultaneous release of GABA from several interneurons activates postsynaptic GABA(B)Rs and that block of GABA(B)Rs increases oscillation frequency. Furthermore, if GABA uptake is inhibited, even GABA released by a single interneuron is enough to activate GABA(B)Rs. This occurs also on cells not directly contacted by that interneuron, indicating that GABA has to overcome uptake and exit the synaptic cleft to reach GABA(B)RS. Thus, activation of extrasynaptic GABA(B)Rs by pooling of GABA is an important mechanism regulating hippocampal network activity.     

Direct presynaptic regulation of GABA/glycine release by kainate receptors in the dorsal horn: an ionotropic mechanism.

In the spinal cord dorsal horn, excitatory sensory fibers terminate adjacent to interneuron terminals. Here, we show that kainate (KA) receptor activation triggered action potential-independent release of GABA and glycine from dorsal horn interneurons. This release was transient, because KA receptors desensitized, and it required Na+ entry and Ca2+ channel activation. KA modulated evoked inhibitory transmission in a dose-dependent, biphasic manner, with suppression being more prominent. In recordings from isolated neuron pairs, this suppression required GABA(B) receptor activation, suggesting that KA-triggered GABA release activated presynaptic GABA(B) autoreceptors. Finally, glutamate released from sensory fibers caused a KA and GABA(B) receptor-dependent suppression of inhibitory transmission in spinal slices. Thus, we show how presynaptic KA receptors are linked to changes in GABA/glycine release and highlight a novel role for these receptors in regulating sensory transmission.     

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.     

Presynaptic effects of biogenic amines modulating synaptic transmission between identified sensory neurons and giant interneurons in the first instar cockroach

Intracellular recording was used to investigate the modulatory effects of serotonin and octopamine on the identified synapses between filiform hair sensory afferents and giant interneurons in the first instar cockroach, Periplaneta americana. Serotonin at 10(-4) mol l(-1) to 10(-3) mol l(-1) reduced the amplitude of the lateral axon-to-ipsilateral giant interneuron 3 excitatory postsynaptic potentials. and octopamine at 10(-4) mol l(-1) increased their amplitude. Similar effects were seen on excitatory postsynaptic potentials in dorsal giant interneuron 6. Several lines of evidence suggest that both substances modulate the amplitude of excitatory postsynaptic potentials by acting presynaptically, rather than on the postsynaptic neuron. The fitting of simple binomial distributions to the postsynaptic potential amplitude histograms suggested that, for both serotonin and octopamine, the number of synaptic release sites was being modulated. Secondly, the amplitudes of miniature excitatory postsynaptic potentials recorded in the presence of tetrodotoxin were unaffected by either modulator. Finally, recordings from contralateral giant interneuron 3, which has two identifiable populations of synaptic inputs, showed that each modulator had a more pronounced effect on excitatory postsynaptic potentials evoked by the lateral axon than on those evoked by the medial axon. Immunocytochemistry confirmed that neuropilar processes containing serotonin are present in close proximity to these synapses.     

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.     

Receptor-induced Ca(2+) signaling in cultured myenteric neurons

We studied the effect of excitatory neurotransmitters (10(-5) M) on the intracellular Ca(2+) concentration ([Ca(2+)](i)) of cultured myenteric neurons. ACh evoked a response in 48.6% of the neurons. This response consisted of a fast and a slow component, respectively mediated by nicotinic and muscarinic receptors, as revealed by specific agonists and antagonists. Substance P evoked a [Ca(2+)](i) rise in 68.2% of the neurons, which was highly dependent on Ca(2+) release from intracellular stores, since after thapsigargin (5 microM) pretreatment only 8% responded. The responses to serotonin, present in 90.7%, were completely blocked by ondansetron (10(-5) M), a 5-HT(3) receptor antagonist. Specific agonists of other serotonin receptors were not able to induce a [Ca(2+)](i) rise. Removing extracellular Ca(2+) abolished all serotonin and fast ACh responses, whereas substance P and slow ACh responses were more persistent. We conclude that ACh-induced signaling involves both nicotinic and muscarinic receptors responsible for a fast and a more delayed component, respectively. Substance P-induced signaling requires functional intracellular Ca(2+) stores, and the 5-HT(3) receptor mediates the serotonin-induced Ca(2+) signaling in cultured myenteric neurons.     

LTS and FS inhibitory interneurons, short-term synaptic plasticity, and cortical circuit dynamics

Somatostatin-expressing, low threshold-spiking (LTS) cells and fast-spiking (FS) cells are two common subtypes of inhibitory neocortical interneuron. Excitatory synapses from regular-spiking (RS) pyramidal neurons to LTS cells strongly facilitate when activated repetitively, whereas RS-to-FS synapses depress. This suggests that LTS neurons may be especially relevant at high rate regimes and protect cortical circuits against over-excitation and seizures. However, the inhibitory synapses from LTS cells usually depress, which may reduce their effectiveness at high rates. We ask: by which mechanisms and at what firing rates do LTS neurons control the activity of cortical circuits responding to thalamic input, and how is control by LTS neurons different from that of FS neurons? We study rate models of circuits that include RS cells and LTS and FS inhibitory cells with short-term synaptic plasticity. LTS neurons shift the RS firing-rate vs. current curve to the right at high rates and reduce its slope at low rates; the LTS effect is delayed and prolonged. FS neurons always shift the curve to the right and affect RS firing transiently. In an RS-LTS-FS network, FS neurons reach a quiescent state if they receive weak input, LTS neurons are quiescent if RS neurons receive weak input, and both FS and RS populations are active if they both receive large inputs. In general, FS neurons tend to follow the spiking of RS neurons much more closely than LTS neurons. A novel type of facilitation-induced slow oscillations is observed above the LTS firing threshold with a frequency determined by the time scale of recovery from facilitation. To conclude, contrary to earlier proposals, LTS neurons affect the transient and steady state responses of cortical circuits over a range of firing rates, not only during the high rate regime; LTS neurons protect against over-activation about as well as FS neurons.     

Cell-type-specific recruitment of amygdala interneurons to hippocampal theta rhythm and noxious stimuli in vivo

Neuronal synchrony in the basolateral amygdala (BLA) is critical for emotional behavior. Coordinated theta-frequency oscillations between the BLA and the hippocampus and precisely timed integration of?salient sensory stimuli in the BLA are involved in?fear conditioning. We characterized GABAergic interneuron types of the BLA and determined their contribution to shaping these network activities. Using in?vivo recordings in rats combined with the anatomical identification of neurons, we found that the firing of BLA interneurons associated with network activities was cell type specific. The firing of calbindin-positive interneurons targeting dendrites was precisely theta-modulated, but other cell types were heterogeneously modulated, including parvalbumin-positive basket cells. Salient sensory stimuli selectively triggered axo-axonic cells firing and inhibited firing of a disctinct projecting interneuron type. Thus, GABA is released onto BLA principal neurons in a time-, domain-, and sensory-specific manner. These specific synaptic actions likely cooperate to promote amygdalo-hippocampal synchrony involved in emotional memory formation.     

Dopaminergic acceleration and GABAergic inhibition in extrinsic neural control of the hermit crab heart

The acceleratory and inhibitory cardio-regulatory nerves of hermit crabs (Aniculus aniculus, Dardanus crassimanus) were studied using histochemical, immunocytochemical and pharmacological tests. Glyoxylic acid-induced fluorescence was observed in two of three axons of the dorsal cardiac nerve. One axon of the nerve showed gamma-aminobutyric acid-like immunoreactivity. Effects of stimulation of cardio-acceleratory axons were blocked by the dopaminergic antagonists, haloperidol and chlorpromazine, but not by cholinergic, adrenergic or serotonergic blockers, suggesting that dopamine is the primary potential candidate for the neurotransmitter of cardio-accelerator neurons. Picrotoxin antagonized inhibition of the cardiac ganglion induced by gammaam-inobutyric acid and by cardio-inhibitory axons. Both small and large ganglionic cells may receive dopaminergic and GABAergic extrinsic neural control.Abbreviations ACh acetylcholine - CA cardio-accelerator - CA1 and CA2 first and second cardio-accelerators - CI cardio-inhibitor - EJP excitatory junction potential - GABA gamma-aminobutyric acid - EPSP excitatory postsynaptic potential - IPSP inhibitory postsynaptic potential - LGC large ganglionic cell - SGC small ganglionic cell - 5-HT serotonin     

Shunting inhibition improves robustness of gamma oscillations in hippocampal interneuron networks by homogenizing firing rates

Networks of GABAergic neurons are key elements in the generation of gamma oscillations in the brain. Computational studies suggested that the emergence of coherent oscillations requires hyperpolarizing inhibition. Here, we show that GABA(A) receptor-mediated inhibition in mature interneurons of the hippocampal dentate gyrus is shunting rather than hyperpolarizing. Unexpectedly, when shunting inhibition is incorporated into a structured interneuron network model with fast and strong synapses, coherent oscillations emerge. In comparison to hyperpolarizing inhibition, networks with shunting inhibition show several advantages. First, oscillations are generated with smaller tonic excitatory drive. Second, network frequencies are tuned to the gamma band. Finally, robustness against heterogeneity in the excitatory drive is markedly improved. In single interneurons, shunting inhibition shortens the interspike interval for low levels of drive but prolongs it for high levels, leading to homogenization of neuronal firing rates. Thus, shunting inhibition may confer increased robustness to gamma oscillations in the brain.