Timing and specificity of feed-forward inhibition within the LGN

Local interneurons provide feed-forward inhibition from retinal ganglion cells (RGCs) to thalamocortical (TC) neurons, but questions remain regarding the timing, magnitude, and functions of this inhibition. Here, we identify two types of inhibition that are suited to play distinctive roles. We recorded excitatory and inhibitory postsynaptic currents (EPSCs/IPSCs) in TC neurons in mouse brain slices and activated individual RGC inputs. In 34% of TC neurons, we identified EPSCs and IPSCs with identical thresholds that were tightly correlated, indicating activation by the same RGC. Such "locked" IPSCs occurred 1 ms after EPSC onset. The remaining neurons had only "nonlocked" inhibition, in which EPSCs and IPSCs had different thresholds, indicating activation by different RGCs. Nonlocked inhibition may refine receptive fields within the LGN by providing surround inhibition. In contrast, dynamic-clamp recordings suggest that locked inhibition improves the precision of synaptically evoked responses in individual TC neurons by eliminating secondary spikes.     

Local gating of information processing through the thalamus

Inhibitory sculpting of afferent signals in the thalamus is exerted by two types of neurons using gamma-amino butyric acid (GABA) as neurotransmitter. Of them, local-circuit neurons exert their functions via two outputs: axons and presynaptic dendrites. In this issue of Neuron, Govindaiah and Cox reveal that synaptic activation of metabotropic glutamate receptors selectively increases the output of presynaptic dendrites of local interneurons in rat visual thalamus, without affecting the axonal output.     

Ivy cells: a population of nitric-oxide-producing, slow-spiking GABAergic neurons and their involvement in hippocampal network activity

In the cerebral cortex, GABAergic interneurons are often regarded as fast-spiking cells. We have identified a type of slow-spiking interneuron that offers distinct contributions to network activity. "Ivy" cells, named after their dense and fine axons innervating mostly basal and oblique pyramidal cell dendrites, are more numerous than the parvalbumin-expressing basket, bistratified, or axo-axonic cells. Ivy cells express nitric oxide synthase, neuropeptide Y, and high levels of GABA(A) receptor alpha1 subunit; they discharge at a low frequency with wide spikes in vivo, yet are distinctively phase-locked to behaviorally relevant network rhythms including theta, gamma, and ripple oscillations. Paired recordings in vitro showed that Ivy cells receive depressing EPSPs from pyramidal cells, which in turn receive slowly rising and decaying inhibitory input from Ivy cells. In contrast to fast-spiking interneurons operating with millisecond precision, the highly abundant Ivy cells express presynaptically acting neuromodulators and regulate the excitability of pyramidal cell dendrites through slowly rising and decaying GABAergic inputs.     

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.     

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.     

Location-dependent effects of inhibition on local spiking in pyramidal neuron dendrites

Cortical computations are critically dependent on interactions between pyramidal neurons (PNs) and a menagerie of inhibitory interneuron types. A key feature distinguishing interneuron types is the spatial distribution of their synaptic contacts onto PNs, but the location-dependent effects of inhibition are mostly unknown, especially under conditions involving active dendritic responses. We studied the effect of somatic vs. dendritic inhibition on local spike generation in basal dendrites of layer 5 PNs both in neocortical slices and in simple and detailed compartmental models, with equivalent results: somatic inhibition divisively suppressed the amplitude of dendritic spikes recorded at the soma while minimally affecting dendritic spike thresholds. In contrast, distal dendritic inhibition raised dendritic spike thresholds while minimally affecting their amplitudes. On-the-path dendritic inhibition modulated both the gain and threshold of dendritic spikes depending on its distance from the spike initiation zone. Our findings suggest that cortical circuits could assign different mixtures of gain vs. threshold inhibition to different neural pathways, and thus tailor their local computations, by managing their relative activation of soma- vs. dendrite-targeting interneurons.     

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     

Kainate receptor activation enhances both tonic and phasic GABA-ergic inhibition in CA1 hippocampal interneurons

Kainate receptor agonists are powerful convulsants and excitotoxins. It has been a lot of controversy around functions of these receptors in the brain. It is shown in this article that kainate enhances evoked GABAergic IPSC (phasic currents) in CA1 interneurons in concentration-dependent manner. The phenomenon is likely to be due to kainate-mediated lowering of the threshold for action potential generation in interneuron axons and increased number of terminals responding to the same stimulus strength. Kainate application also induced an enhancement in tonic GABAergic conductance. This phenomenon can be attributed to massive extracellular GABA accumulation caused by interneuron firing in the presence of kainate. Extracellular GABA also shunts synaptic currents by activating tonic conductance as well as desensitizing synaptic GABAA receptors. Thus, the enhancement of the evoked IPSCs by 1 microM kainate was complicated by early and transient decrease. The kainate receptor-mediated enhancement of GABAergic tonic and phasic signalling to interneurons can contribute to the depression of GABAergic transmission to pyramidal neurons. The consequence of this phenomenon may play a major role in the epileptogenic action of this agent.     

Thalamocortical control of feed-forward inhibition in awake somatosensory 'barrel' cortex

Intracortical inhibition plays a role in shaping sensory cortical receptive fields and is mediated by both feed-forward and feedback mechanisms. Feed-forward inhibition is the faster of the two processes, being generated by inhibitory interneurons driven by monosynaptic thalamocortical (TC) input. In principle, feed-forward inhibition can prevent targeted cortical neurons from ever reaching threshold when TC input is weak. To do so, however, inhibitory interneurons must respond to TC input at low thresholds and generate spikes very quickly. A powerful feed-forward inhibition would sharpen the tuning characteristics of targeted cortical neurons, and interneurons with sensitive and broadly tuned receptive fields could mediate this process. Suspected inhibitory interneurons (SINs) with precisely these properties are found in layer 4 of the somatosensory (S1) 'barrel' cortex of rodents and rabbits. These interneurons lack the directional selectivity seen in most cortical spiny neurons and in ventrobasal TC afferents, but are much more sensitive than cortical spiny neurons to low-amplitude whisker displacements. This paper is concerned with the activation of S1 SINs by TC impulses, and with the consequences of this activation. Multiple TC neurons and multiple S1 SINs were simultaneously studied in awake rabbits, and cross-correlation methods were used to examine functional connectivity. The results demonstrate a potent, temporally precise, dynamic and highly convergent/divergent functional input from ventrobasal TC neurons to SINs of the topographically aligned S1 barrel. Whereas the extensive pooling of convergent TC inputs onto SINs generates sensitive and broadly tuned inhibitory receptive fields, the potent TC divergence onto many SINs generates sharply synchronous activity among these elements. This TC feed-forward inhibitory network is well suited to provide a fast, potent, sensitive and broadly tuned inhibition of targeted spiny neurons that will suppress spike generation following all but the most optimal feed-forward excitatory inputs.     

Calretinin-containing interneurons innervate both principal cells and interneurons in the CA1 region of the human hippocampus

Hippocampal interneurons consist of functionally diverse cell types, most of them target the dendrites or perisomatic region of pyramidal cells with a few exceptions, like the calretinin-containing cells in the rat: they selectively innervate other interneurons. However, no electron microscopic data are available about the synaptic connections of calretinin-immunoreactive neurons in the human hippocampus. We aimed to provide these data to establish whether interneuron-selective interneurons indeed represent an essential feature of hippocampal circuits across distant species. Two types of calretinin-immunostained terminals were found in the CA1 region: one of them presumably derived from the thalamic reuniens nucleus, and established asymmetric synapses on dendrites and spines. The other type originating from local interneurons formed symmetric synapses on both pyramidal and interneuron dendrites. Distribution of postsynaptic targets showed that 26.8% of the targets were CR-positive interneuron dendrites, and 25.2% proved to be proximal pyramidal dendrites. CR-negative interneuron dendrites were also contacted (12.4%). Small caliber postsynaptic dendrites were not classified (28%). Somata were rarely contacted (7.6%). The present data suggest that calretinin-positive boutons do show a preference for other interneurons, but a considerable proportion of the targets are pyramidal cells. We propose that interneuron-selective inhibitory cells exist in the human Ammon's horn, and boutons innervating pyramidal cells derive from another cell type that might not exist in rodents.     

In vivo imaging reveals dendritic targeting of laminated afferents by zebrafish retinal ganglion cells

Targeting of axons and dendrites to particular synaptic laminae is an important mechanism by which precise patterns of neuronal connectivity are established. Although axons target specific laminae during development, dendritic lamination has been thought to occur largely by pruning of inappropriately placed arbors. We discovered by in vivo time-lapse imaging that retinal ganglion cell (RGC) dendrites in zebrafish show growth patterns implicating dendritic targeting as a mechanism for contacting appropriate synaptic partners. Populations of RGCs labeled in transgenic animals establish distinct dendritic strata sequentially, predominantly from the inner to outer retina. Imaging individual cells over successive days confirmed that multistratified RGCs generate strata sequentially, each arbor elaborating within a specific lamina. Simultaneous imaging of RGCs and subpopulations of presynaptic amacrine interneurons revealed that RGC dendrites appear to target amacrine plexuses that had already laminated. Dendritic targeting of prepatterned afferents may thus be a novel mechanism for establishing proper synaptic connectivity.     

Pathway-specific genetic attenuation of glutamate release alters select features of competition-based visual circuit refinement

A hallmark of mammalian neural circuit development is the refinement of initially imprecise connections by competitive activity-dependent processes. In the developing visual system retinal ganglion cell (RGC) axons from the two eyes undergo activity-dependent competition for territory in the dorsal lateral geniculate nucleus (dLGN). The direct contributions of synaptic transmission to this process, however, remain unclear. We used a genetic approach to reduce glutamate release selectively from ipsilateral-projecting RGCs and found that their release-deficient axons failed to exclude competing axons from the ipsilateral eye territory in the dLGN. Nevertheless, the release-deficient axons consolidated and maintained their normal amount of dLGN territory, even in the face of fully active competing axons. These results show that during visual circuit refinement glutamatergic transmission plays a direct role in excluding competing axons from inappropriate target regions, but they argue that consolidation and maintenance of axonal territory are largely insensitive to alterations in synaptic activity levels.     

The organization of plurisegmental mechanosensitive interneurons in the central nervous system of the wandering spider Cupiennius salei

Summary In spiders the bulk of the central nervous system (CNS) consists of fused segmental ganglia traversed by longitudinal tracts, which have precise relationships with sensory neuropils and which contain the fibers of large plurisegmental interneurons. The responses of these interneurons to various mechanical stimuli were studied electrophysiologically, and their unilateral or bilateral structure was revealed by intracellular staining. Unilateral interneurons visit all the neuromeres on one side of the CNS. They receive mechanosensory input either from a single leg or from all ipsilateral legs via sensory neurons that invade leg neuromeres and project into specific longitudinal tracts. The anatomical organization of unilateral interneurons suggests that their axons impart their information to all ipsilateral leg neuromeres. Bilateral interneurons are of two kinds, symmetric and asymmetric neurons. The latter respond to stimulation of all legs on one side of the body, having their dendrites amongst sensory tracts of the same side of the CNS. Anatomical evidence suggests that their terminals invade all four contralateral leg neuromeres. Bilaterally symmetrical plurisegmental interneurons have dendritic arborizations in both halves of the fused ventral ganglia. They respond to the stimulation of any of the 8 legs. A third class of cells, the ascending neurons have unilateral or bilateral dendritic arborizations in the fused ventral ganglia and show blebbed axons in postero-ventral regions of the brain. Their response characteristics are similar to those of other plurisegmental interneurons. Descending neurons have opposite structural polarity, arising in the brain and terminating in segmental regions of the fused ventral ganglia. Descending neurons show strong responses to visual stimulation. Approximately 50% of all the recorded neurons respond exclusively to stimulation of a single type of mechanoreceptor (either tactile hairs, or trichobothria, or slit sensilla), while the rest respond to stimulation of a variety of sensilla. However, these functional differences are not obviously reflected by the anatomy. The functional significance of plurisegmental interneurons is discussed with respect to sensory convergence and the coordination of motor output to the legs. A comparison between the response properties of certain plurisegmental interneurons and their parent longitudinal tracts suggests that the tracts themselves do not reflect a modality-specific organization.Abbreviations BPI bilateral plurisegmental interneuron - CNS central nervous system - FVG fused ventral ganglia - LT longitudinal tract - PI plurisegmental interneuron - PSTH peristimulus timehistogram - UPI unilateral plurisegmental interneuron     

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.     

Spike-dependent calcium influx in dendrites of the cricket giant interneuron

Identified wind-sensitive giant interneurons in the cricket's cercal sensory system integrate cercal afferent signals and release an avoidance behavior. A calcium-imaging technique was applied to the giant interneurons to examine the presence of the voltage-dependent Ca(2+) channels (VDCCs) in their dendrites. We found that presynaptic stimuli to the cercal sensory nerve cords elevated the cytosolic Ca(2+) concentration ([Ca(2+)](i)) in the dendrites of the giant interneurons. The dendritic Ca(2+) rise coincided with the spike burst of the giant interneurons, and the rate of Ca(2+) rise depended on the frequency of the action potentials. These results suggest that the action potentials directly caused [Ca(2+)](i) increase. Observation of the [Ca(2+)](i) elevation induced by depolarizing current injection demonstrates the presence of the VDCCs in the dendrites. Although hyperpolarizing current injection into the giant interneuron suppressed action potential generation, EPSPs could induce no [Ca(2+)](i) increase. This result means that ligand-gated channels do not contribute to the synaptically stimulated Ca(2+) elevation. On the other hand, antidromically stimulated spikes also increased [Ca(2+)](i) in all cellular regions including the dendrites. And bath application of a mixture of Ni(2+), Co(2+), and Cd(2+) or tetrodotoxin inhibited the [Ca(2+)](i) elevation induced by the antidromic stimulation. From these findings, we suppose that the axonal spikes antidromically propagate and induce the Ca(2+) influx via VDCCs in the dendrites. The spike-dependent Ca(2+) elevation may regulate the sensory signals processing via second-messenger cascades in the giant interneurons.     

Perisomatic GABA release and thalamocortical integration onto neocortical excitatory cells are regulated by neuromodulators

Neuromodulators such as acetylcholine, serotonin, and noradrenaline are powerful regulators of neocortical activity. Although it is well established that cortical inhibition is the target of these modulations, little is known about their effects on GABA release from specific interneuron types. This knowledge is necessary to gain a mechanistic understanding of the actions of neuromodulators because different interneuron classes control specific aspects of excitatory cell function. Here, we report that GABA release from fast-spiking (FS) cells, the most prevalent interneuron subtype in neocortex, is robustly inhibited following activation of muscarinic, serotonin, adenosine, and GABA(B) receptors--an effect that regulates FS cell control of excitatory neuron firing. The potent muscarinic inhibition of GABA release from FS cells suppresses thalamocortical feedforward inhibition. This is supplemented by the muscarinic-mediated depolarization of thalamo-recipient excitatory neurons and the nicotinic enhancement of thalamic input onto these neurons to promote thalamocortical excitation.     

Neurogliaform cells: neurochemistry, spatial arrangement, and their role in the neocortical inhibitory system

The neurogliaform cells (NGFC) localized in area 4 of the human motor cortex were found to express choline acetyl transferase (ChAT), GABA, and calbindin. ChAT-positive neurons were located in cortical layer II. Their dendrites lay in a close proximity to those of pyramid cells, neighbouring neurogliaform cells, and bodies and dendrites of other cortical neurons. The NGFCs revealed by Golgi staining fell into two groups. Cells of the first group had locally (within cortical layer II) spreading axons, while those of the second group had axons extending into the adjacent layers. Neurochemical heterogeneity of NGFCs is discussed in the context of information processing in cortical modules and interaction of excitatory and inhibitory interneurons.     

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.     

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.