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.     

Interneuron networks in the hippocampus

The hippocampus has contributed enormously to our understanding of the operation of elemental brain circuits, not least through the classification of forebrain interneurons. Understanding the operation of interneuron networks however requires not only a wiring diagram that describes the innervation and postsynaptic targets of different GABAergic cells, but also an appreciation of the temporal dimension. Interneurons differ extensively in their intrinsic firing rates, their recruitment in different brain rhythms, and in their synaptic kinetics. Furthermore, in common with principal neurons, both the synapses innervating interneurons and the synapses made by these cells are highly modifiable, reflecting both their recent or remote use (short-term and long-term plasticity) and the action of extracellular messengers. This review examines recent progress in understanding how different hippocampal interneuron networks contribute to feedback and feed-forward inhibition at different timescales.     

Target neuron specification of short-term synaptic facilitation and depression in the cricket CNS

We investigated the role of retrograde signals in the regulation of short-term synaptic depression and facilitation by characterizing the form of plasticity expressed at novel synapses on four giant interneurons in the cricket cercal sensory system. We induced the formation of novel synapses by transplanting a mesothoracic leg and its associated sensory neurons to the cricket terminal abdominal segment. Axons of ectopic leg sensory neurons regenerated and innervated the host terminal abdominal ganglion forming monosynaptic connections with the medial giant interneuron (MGI), lateral giant interneuron (LGI), and interneurons 7-1a and 9-2a. The plasticity expressed by these synapses was characterized by stimulating a sensory neuron with pairs of stimuli at various frequencies or with trains of 10 stimuli delivered at 100 Hz and measuring the change in excitatory postsynaptic potential amplitude recorded in the postsynaptic neuron. Novel synapses of a leg tactile hair on 7-1a depressed, as did control synapses of cercal sensory neurons on this interneuron. Novel synapses of leg campaniform sensilla (CS) sensory neurons on MGI, like MGI's control synapses, always facilitated. The form of plasticity expressed by novel synapses is thus consistent with that observed at control synapses. Leg CS synapses with 9-2a also facilitated; however, the plasticity expressed by these sensory neurons is dependent on the identity of the postsynaptic cell since the synapses these same sensory neurons formed with LGI always depressed. We conclude that the form of plasticity expressed at these synaptic connections is determined retrogradely by the postsynaptic cell. © 1998 John Wiley & Sons, Inc. J Neurobiol 37: 700–714, 1998     

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     

Dapper Antagonist of Catenin-1 Cooperates with Dishevelled-1 during Postsynaptic Development in Mouse Forebrain GABAergic Interneurons

Synaptogenesis has been extensively studied along with dendritic spine development in glutamatergic pyramidal neurons, however synapse development in cortical interneurons, which are largely aspiny, is comparatively less well understood. Dact1, one of 3 paralogous Dact (Dapper/Frodo) family members in mammals, is a scaffold protein implicated in both the Wnt/β-catenin and the Wnt/Planar Cell Polarity pathways. We show here that Dact1 is expressed in immature cortical interneurons. Although Dact1 is first expressed in interneuron precursors during proliferative and migratory stages, constitutive Dact1 mutant mice have no major defects in numbers or migration of these neurons. However, cultured cortical interneurons derived from these mice have reduced numbers of excitatory synapses on their dendrites. We selectively eliminated Dact1 from mouse cortical interneurons using a conditional knock-out strategy with a Dlx-I12b enhancer-Cre allele, and thereby demonstrate a cell-autonomous role for Dact1 during postsynaptic development. Confirming this cell-autonomous role, we show that synapse numbers in Dact1 deficient cortical interneurons are rescued by virally-mediated re-expression of Dact1 specifically targeted to these cells. Synapse numbers in these neurons are also rescued by similarly targeted expression of the Dact1 binding partner Dishevelled-1, and partially rescued by expression of Disrupted in Schizophrenia-1, a synaptic protein genetically implicated in susceptibility to several major mental illnesses. In sum, our results support a novel cell-autonomous postsynaptic role for Dact1, in cooperation with Dishevelled-1 and possibly Disrupted in Schizophrenia-1, in the formation of synapses on cortical interneuron dendrites.     

Synaptic interactions between neurons involved in the production of abdominal posture in crayfish

Summary Pairs of neurons that produce or influence motor outputs in the abdominal positioning system of the crayfish (Procambarus clarkii) were impaled in isolated nerve cords with Lucifer Yellow-filled microelectrodes to determine their morphologies and the nature and extent of the synaptic interactions between them. Although the motor programs for positional adjustments can be produced by directly stimulating single interneurons, we found extensive interactions between these neurons, often involving the recruitment of one interneuron by another. The data indicate that the positioning interneurons do not operate as labelled lines, each independently producing a discrete position. Pairs of interneurons, each producing similar motor outputs when activated, were often found to be connected by unidirectional excitatory synapses. In contrast, central inhibition was commonly found between pairs of interneurons that produced antagonistic motor effects. Finally, the unidirectional interactions between positioning interneurons revealed a hierarchy of at least two tiers in this system. Based on these observations, we suggest that abdominal positioning in crustaceans is produced by constellations of interacting interneurons.Abbreviations FPI flexion-producing interneuron - EPI extension-producing interneuron - LI local interneuron - SFMN slow flexor motoneuron - SEMN slow extensor motoneuron     

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.     

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.     

State transitions through inhibitory interneurons in a cortical network model

Inhibitory interneurons shape the spiking characteristics and computational properties of cortical networks. Interneuron subtypes can precisely regulate cortical function but the roles of interneuron subtypes for promoting different regimes of cortical activity remains unclear. Therefore, we investigated the impact of fast spiking and non-fast spiking interneuron subtypes on cortical activity using a network model with connectivity and synaptic properties constrained by experimental data. We found that network properties were more sensitive to modulation of the fast spiking population, with reductions of fast spiking excitability generating strong spike correlations and network oscillations. Paradoxically, reduced fast spiking excitability produced a reduction of global excitation-inhibition balance and features of an inhibition stabilised network, in which firing rates were driven by the activity of excitatory neurons within the network. Further analysis revealed that the synaptic interactions and biophysical features associated with fast spiking interneurons, in particular their rapid intrinsic response properties and short synaptic latency, enabled this state transition by enhancing gain within the excitatory population. Therefore, fast spiking interneurons may be uniquely positioned to control the strength of recurrent excitatory connectivity and the transition to an inhibition stabilised regime. Overall, our results suggest that interneuron subtypes can exert selective control over excitatory gain allowing for differential modulation of global network state.     

Whole-Brain Mapping of Inputs to Projection Neurons and Cholinergic Interneurons in the Dorsal Striatum

The dorsal striatum integrates inputs from multiple brain areas to coordinate voluntary movements, associative plasticity, and reinforcement learning. Its projection neurons consist of the GABAergic medium spiny neurons (MSNs) that express dopamine receptor type 1 (D1) or dopamine receptor type 2 (D2). Cholinergic interneurons account for a small portion of striatal neuron populations, but they play important roles in striatal functions by synapsing onto the MSNs and other local interneurons. By combining the modified rabies virus with specific Cre- mouse lines, a recent study mapped the monosynaptic input patterns to MSNs. Because only a small number of extrastriatal neurons were labeled in the prior study, it is important to reexamine the input patterns of MSNs with higher labeling efficiency. Additionally, the whole-brain innervation pattern of cholinergic interneurons remains unknown. Using the rabies virus-based transsynaptic tracing method in this study, we comprehensively charted the brain areas that provide direct inputs to D1-MSNs, D2-MSNs, and cholinergic interneurons in the dorsal striatum. We found that both types of projection neurons and the cholinergic interneurons receive extensive inputs from discrete brain areas in the cortex, thalamus, amygdala, and other subcortical areas, several of which were not reported in the previous study. The MSNs and cholinergic interneurons share largely common inputs from areas outside the striatum. However, innervations within the dorsal striatum represent a significantly larger proportion of total inputs for cholinergic interneurons than for the MSNs. The comprehensive maps of direct inputs to striatal MSNs and cholinergic interneurons shall assist future functional dissection of the striatal circuits.     

Neuropeptide S-mediated facilitation of synaptic transmission enforces subthreshold theta oscillations within the lateral amygdala

The neuropeptide S (NPS) receptor system modulates neuronal circuit activity in the amygdala in conjunction with fear, anxiety and the expression and extinction of previously acquired fear memories. Using in vitro brain slice preparations of transgenic GAD67-GFP (Δneo) mice, we investigated the effects of NPS on neural activity in the lateral amygdala as a key region for the formation and extinction of fear memories. We are able to demonstrate that NPS augments excitatory glutamatergic synaptic input onto both projection neurons and interneurons of the lateral amygdala, resulting in enhanced spike activity of both types of cells. These effects were at least in part mediated by presynaptic mechanisms. In turn, inhibition of projection neurons by local interneurons was augmented by NPS, and subthreshold oscillations were strengthened, leading to their shift into the theta frequency range. These data suggest that the multifaceted effects of NPS on amygdaloid circuitry may shape behavior-related network activity patterns in the amygdala and reflect the peptide's potent activity in various forms of affective behavior and emotional memory.     

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.     

Synaptic relationships between GABA-immunoreactive neurons and an identified uniglomerular projection neuron in the antennal lobe of Periplaneta americana: a double-labeling electron microscopic study

Two types of central neurons in the antennal lobe of the American cockroach Periplaneta americana were labeled with a combination of two specific markers. Their synaptic contacts were characterized and their distribution on the neurons examined. A uniglomerular pheromone-sensitive projection neuron with dendritic arbor in the male-specific macroglomerulus (attractant neuron) was characterized physiologically by intracellular recording and then filled with biocytin, which was converted to a marker for this individual neuron by a preembedding procedure. In a postembedding procedure local, multiglomerular interneurons were marked by immunogold labeling of GABA. Two kinds of synaptic contacts were found on the attractant neuron. (i) Input synapses from GABA-immunoreactive profiles. There were many of these, which (together with results of previous studies) suggests that local interneurons mediate polysynaptic transmission from antennal receptor fibers to the projection neuron. (ii) Output synapses onto GABA-immunoreactive profiles and onto non-identified neurons. These contacts indicate that signals generated by the projection neurons in a given glomerulus are passed back to multiglomerular interneurons and hence are also transmitted to other glomeruli.     

Quantitative Organization of GABAergic Synapses in the Molecular Layer of the Mouse Cerebellar Cortex

In the cerebellar cortex, interneurons of the molecular layer (stellate and basket cells) provide GABAergic input to Purkinje cells, as well as to each other and possibly to other interneurons. GABAergic inhibition in the molecular layer has mainly been investigated at the interneuron to Purkinje cell synapse. In this study, we used complementary subtractive strategies to quantitatively assess the ratio of GABAergic synapses on Purkinje cell dendrites versus those on interneurons. We generated a mouse model in which the GABA_A receptor α1 subunit (GABA_ARα1) was selectively removed from Purkinje cells using the Cre/loxP system. Deletion of the α1 subunit resulted in a complete loss of GABA_AR aggregates from Purkinje cells, allowing us to determine the density of GABA_AR clusters in interneurons. In a complementary approach, we determined the density of GABA synapses impinging on Purkinje cells using α-dystroglycan as a specific marker of inhibitory postsynaptic sites. Combining these inverse approaches, we found that synapses received by interneurons represent approximately 40% of all GABAergic synapses in the molecular layer. Notably, this proportion was stable during postnatal development, indicating synchronized synaptogenesis. Based on the pure quantity of GABAergic synapses onto interneurons, we propose that mutual inhibition must play an important, yet largely neglected, computational role in the cerebellar cortex.     

Synaptic relationships between GABA-immunoreactive neurons and an identified uniglomerular projection neuron in the antennal lobe of Periplaneta americana: a double-labeling electron microscopic study

Summary Two types of central neurons in the antennal lobe of the American cockroach Periplaneta americana were labeled with a combination of two specific markers. Their synaptic contacts were characterized and their distribution on the neurons examined. A uniglomerular pheromone-sensitive projection neuron with dendritic arbor in the male-specific macroglomerulus (attractant neuron) was characterized physiologically by intracellular recording and then filled with biocytin, which was converted to a marker for this individual neuron by a preembedding procedure. In a postembedding procedure local, multiglomerular interneurons were marked by immunogold labeling of GABA. Two kinds of synaptic contacts were found on the attractant neuron. (i) Input synapses from GABA-immunoreactive profiles. There were many of these, which (together with results of previous studies) suggests that local interneurons mediate polysynaptic transmission from antennal receptor fibers to the projection neuron. (ii) Output synapses onto GABA-immunoreactive profiles and onto non-identified neurons. These contacts indicate that signals generated by the projection neurons in a given glomerulus are passed back to multiglomerular interneurons and hence are also transmitted to other glomeruli.     

A new regime for highly robust gamma oscillation with co-exist of accurate and weak synchronization in excitatory–inhibitory networks

A great number of biological experiments show that gamma oscillation occurs in many brain areas after the presentation of stimulus. The neural systems in these brain areas are highly heterogeneous. Specifically, the neurons and synapses in these neural systems are diversified; the external inputs and parameters of these neurons and synapses are heterogeneous. How the gamma oscillation generated in such highly heterogeneous networks remains a challenging problem. Aiming at this problem, a highly heterogeneous complex network model that takes account of many aspects of real neural circuits was constructed. The network model consists of excitatory neurons and fast spiking interneurons, has three types of synapses (GABA_A, AMPA, and NMDA), and has highly heterogeneous external drive currents. We found a new regime for robust gamma oscillation, i.e. the oscillation in inhibitory neurons is rather accurate but the oscillation in excitatory neurons is weak, in such highly heterogeneous neural networks. We also found that the mechanism of the oscillation is a mixture of interneuron gamma (ING) and pyramidal-interneuron gamma (PING). We explained the mixture ING and PING mechanism in a consistent-way by a compound post-synaptic current, which has a slowly rising-excitatory stage and a sharp decreasing-inhibitory stage.     

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.     

Investigation of spinal neuronal mechanisms of movement control systems

Morphological and electrophysiological investigations of the means whereby the principal descending motor systems (the cortico-, rubro-, reticulo-, and vestibulo-spinal tracts) are connected with the segmental interneuronal apparatus and motoneurons show that these connections can be based on two different principles. Descending systems either activate motoneurons directly (monosynaptically) or are connected primarily with various interneuron systems, exerting their influence in that case by regulating the activity of simpler or more complex spinal mechanisms. The older descending system (reticulo- and vestibulo-spinal) possess a monosynaptic excitatory action of motoneurons; the evolutionarily newer descending systems, which transmit the most complex motor signals from the cerebral and cerebellar cortex to the spinal cord (cortico- and rubro-spinal), terminate synaptically in every case on interneurons. It is only in primates that a few cortico-spinal fibers form monosynaptic connections with motoneurons. The chief ways of action of the descending systems on interneurons are: control of the afferent inflow into the interneuron system by presynaptic inhibition of the corresponding synapses; control of the interneuron system by postsynaptic interaction with afferent influences; control of motoneurons through the specialized interneuron apparatus. The investigation shows that the last of these mechanisms functions in the cortico- and rubro-spinal, and possibly also in the reticulo- and vestibulo-spinal systems. The functional role of the various means of connection of the descending systems with the spinal neurons in the system of movement control is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 2, No. 2, pp. 189–202, March–April, 1970.