Development of an Inhibitory Interneuronal Circuit in the Embryonic Spinal Cord

2005 ◽  
Vol 93 (5) ◽  
pp. 2922-2933 ◽  
Author(s):  
Huaying Xu ◽  
Patrick J. Whelan ◽  
Peter Wenner
Keyword(s):  
Cell Types ◽  
Ventral Root ◽  
Network Activity ◽  
Inhibitory Interneurons ◽  
Neurotransmitter Receptor ◽  
Embryonic Spinal Cord ◽  
Root Response ◽  
E6 And E7 ◽  
Recurrent Collaterals ◽  
Ventrolateral Funiculus

Locally projecting inhibitory interneurons play a crucial role in the patterning and timing of network activity. However, because of their relative inaccessibility, little is known about their development or incorporation into circuits. In this study, we characterized the functional onset, neurotransmitters, rostrocaudal spread, and funicular distribution of one such spinal interneuronal circuit during development. The R-interneuron is the avian homologue of the mammalian Renshaw cell. Both cell types receive input from motoneuron recurrent collaterals and make direct connections back onto motoneurons. By stimulating motoneurons projecting in a given ventral root and recording the response in adjacent ventral roots, we demonstrate that the R-interneuron circuit becomes functional between embryonic day 6 (E6) and E7. This ventral root response is observed at E11 and at E14 until it can no longer be detected at E16. Using bath-applied neurotransmitter receptor antagonists, we were able to demonstrate that the circuit is predominately nicotinic and GABAergic from E7.5 to E15. We also found a glutamatergic component to the pathway throughout this developmental period. The R-interneuron projects three or more segments both rostrally and caudally through the ventrolateral funiculus. The distribution of this circuit may become more locally focused between E7.5 and E15.

Engrailed-1 and netrin-1 regulate axon pathfinding by association interneurons that project to motor neurons

Development ◽  
1999 ◽  
Vol 126 (19) ◽  
pp. 4201-4212 ◽  
Author(s):  
H. Saueressig ◽  
J. Burrill ◽  
M. Goulding
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Axon Growth ◽  
Cell Types ◽  
Second Phase ◽  
Axon Pathfinding ◽  
Cell Type Specific ◽  
Embryonic Spinal Cord ◽  
Ventrolateral Funiculus

During early development, multiple classes of interneurons are generated in the spinal cord including association interneurons that synapse with motor neurons and regulate their activity. Very little is known about the molecular mechanisms that generate these interneuron cell types, nor is it known how axons from association interneurons are guided toward somatic motor neurons. By targeting the axonal reporter gene τ-lacZ to the En1 locus, we show the cell-type-specific transcription factor Engrailed-1 (EN1) defines a population of association neurons that project locally to somatic motor neurons. These EN1 interneurons are born early and their axons pioneer an ipsilateral longitudinal projection in the ventral spinal cord. The EN1 interneurons extend axons in a stereotypic manner, first ventrally, then rostrally for one to two segments where their axons terminate close to motor neurons. We show that the growth of EN1 axons along a ventrolateral pathway toward motor neurons is dependent on netrin-1 signaling. In addition, we demonstrate that En1 regulates pathfinding and fasciculation during the second phase of EN1 axon growth in the ventrolateral funiculus (VLF); however, En1 is not required for the early specification of ventral interneuron cell types in the embryonic spinal cord.

Developmental Reorganization of the Output of a GABAergic Interneuronal Circuit

2007 ◽  
Vol 97 (4) ◽  
pp. 2769-2779 ◽  
Author(s):  
Huaying Xu ◽  
Arthur Clement ◽  
Terrence Michael Wright ◽  
Peter Wenner
Keyword(s):  
Spinal Cord ◽  
Chick Embryo ◽  
Synaptic Input ◽  
Ventral Root ◽  
Network Activity ◽  
Inhibitory Interneurons ◽  
Optical Studies ◽  
Adjacent Segments ◽  
Whole Cell Recordings ◽  
Stimulation Of

Locally projecting inhibitory interneurons play a crucial role in the patterning and timing of network activity. However, because of their relative inaccessibility, little is known about their development or incorporation into circuits. In this report we demonstrate that the GABAergic R-interneuron circuit undergoes a reorganization in the chick embryo spinal cord between embryonic days 8 and 15 (E8 and E15). R-interneurons receive synaptic input from and project back to motoneurons. By stimulating motoneurons projecting in one ventral root and recording the disynaptic response from motoneurons in adjacent segments, we show that the output of the R-interneuron circuit is reorganized during development. After stimulation of the LS2 ventral root, disynaptic responses observed in whole cell recordings became more common and stronger for LS3 motoneurons and less common for the more distant LS4 motoneurons from E8 to E10. Optical studies demonstrated that R-interneurons activated by LS2 stimulation were restricted to the LS2 segment and had a small glutamatergic component at both E8 and E10, but that more R-interneurons were activated within the segment by E10. The recruitment of more LS2 R-interneurons at E10 is likely to contribute to stronger projections to LS3 motoneurons, but the fact that fewer LS4 motoneurons receive this input is more consistent with a functional refinement of the more distant projection of the GABAergic R-interneuron. Interestingly, this pattern of reorganization was not observed throughout the rostrocaudal extent of the cord, introducing the possibility that refinement could serve to remove connections between functionally unrelated interneurons and motoneurons.

scholarly journals Btbd11 is an inhibitory interneuron specific synaptic scaffolding protein that supports excitatory synapse structure and function

2021 ◽  
Author(s):  
Alexei M. Bygrave ◽  
Ayesha Sengupta ◽  
Ella P. Jackert ◽  
Mehroz Ahmed ◽  
Beloved Adenuga ◽  
...  
Keyword(s):  
Inhibitory Interneuron ◽  
Nmda Receptor Antagonist ◽  
Specific Protein ◽  
Network Activity ◽  
Scaffolding Protein ◽  
Inhibitory Interneurons ◽  
Cell Type ◽  
Cell Type Specific

Synapses in the brain exhibit cell–type–specific differences in basal synaptic transmission and plasticity. Here, we evaluated cell–type–specific differences in the composition of glutamatergic synapses, identifying Btbd11, as an inhibitory interneuron–specific synapse–enriched protein. Btbd11 is highly conserved across species and binds to core postsynaptic proteins including Psd–95. Intriguingly, we show that Btbd11 can undergo liquid–liquid phase separation when expressed with Psd–95, supporting the idea that the glutamatergic post synaptic density in synapses in inhibitory and excitatory neurons exist in a phase separated state. Knockout of Btbd11 from inhibitory interneurons decreased glutamatergic signaling onto parvalbumin–positive interneurons. Further, both in vitro and in vivo, we find that Btbd11 knockout disrupts network activity. At the behavioral level, Btbd11 knockout from interneurons sensitizes mice to pharmacologically induced hyperactivity following NMDA receptor antagonist challenge. Our findings identify a cell–type–specific protein that supports glutamatergic synapse function in inhibitory interneurons–with implication for circuit function and animal behavior.

Two Dynamically Distinct Inhibitory Networks in Layer 4 of the Neocortex

2003 ◽  
Vol 90 (5) ◽  
pp. 2987-3000 ◽  
Author(s):  
Michael Beierlein ◽  
Jay R. Gibson ◽  
Barry W. Connors
Keyword(s):  
Barrel Cortex ◽  
Dynamic Properties ◽  
Inhibitory Synapses ◽  
Projection Neurons ◽  
Inhibitory Interneurons ◽  
Short Term ◽  
Layer 4 ◽  
Recurrent Collaterals ◽  
Chemical Synapses ◽  
Excitatory And Inhibitory Synapses

Normal operations of the neocortex depend critically on several types of inhibitory interneurons, but the specific function of each type is unknown. One possibility is that interneurons are differentially engaged by patterns of activity that vary in frequency and timing. To explore this, we studied the strength and short-term dynamics of chemical synapses interconnecting local excitatory neurons (regular-spiking, or RS, cells) with two types of inhibitory interneurons: fast-spiking (FS) cells, and low-threshold spiking (LTS) cells of layer 4 in the rat barrel cortex. We also tested two other pathways onto the interneurons: thalamocortical connections and recurrent collaterals from corticothalamic projection neurons of layer 6. The excitatory and inhibitory synapses interconnecting RS cells and FS cells were highly reliable in response to single stimuli and displayed strong short-term depression. In contrast, excitatory and inhibitory synapses interconnecting the RS and LTS cells were less reliable when initially activated. Excitatory synapses from RS cells onto LTS cells showed dramatic short-term facilitation, whereas inhibitory synapses made by LTS cells onto RS cells facilitated modestly or slightly depressed. Thalamocortical inputs strongly excited both RS and FS cells but rarely and only weakly contacted LTS cells. Both types of interneurons were strongly excited by facilitating synapses from axon collaterals of corticothalamic neurons. We conclude that there are two parallel but dynamically distinct systems of synaptic inhibition in layer 4 of neocortex, each defined by its intrinsic spiking properties, the short-term plasticity of its chemical synapses, and (as shown previously) an exclusive set of electrical synapses. Because of their unique dynamic properties, each inhibitory network will be recruited by different temporal patterns of cortical activity.

scholarly journals Recruitment of an inhibitory hippocampal network after bursting in a single granule cell

2007 ◽  
Vol 104 (18) ◽  
pp. 7640-7645 ◽  
Author(s):  
Masahiro Mori ◽  
Beat H. Gähwiler ◽  
Urs Gerber
Keyword(s):  
Pyramidal Cell ◽  
Granule Cell ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Pyramidal Cells ◽  
Network Activity ◽  
Inhibitory Input ◽  
Inhibitory Interneurons ◽  
Failure Rates ◽  
Ca3 Pyramidal Cells

The hippocampal CA3 area, an associational network implicated in memory function, receives monosynaptic excitatory as well as disynaptic inhibitory input through the mossy-fiber axons of the dentate granule cells. Synapses made by mossy fibers exhibit low release probability, resulting in high failure rates at resting discharge frequencies of 0.1 Hz. In recordings from functionally connected pairs of neurons, burst firing of a granule cell increased the probability of glutamate release onto both CA3 pyramidal cells and inhibitory interneurons, such that subsequent low-frequency stimulation evoked biphasic excitatory/inhibitory responses in a CA3 pyramidal cell, an effect lasting for minutes. Analysis of the unitary connections in the circuit revealed that granule cell bursting caused powerful activation of an inhibitory network, thereby transiently suppressing excitatory input to CA3 pyramidal cells. This phenomenon reflects the high incidence of spike-to-spike transmission at granule cell to interneuron synapses, the numerically much greater targeting by mossy fibers of inhibitory interneurons versus principal cells, and the extensively divergent output of interneurons targeting CA3 pyramidal cells. Thus, mossy-fiber input to CA3 pyramidal cells appears to function in three distinct modes: a resting mode, in which synaptic transmission is ineffectual because of high failure rates; a bursting mode, in which excitation predominates; and a postbursting mode, in which inhibitory input to the CA3 pyramidal cells is greatly enhanced. A mechanism allowing the transient recruitment of inhibitory input may be important for controlling network activity in the highly interconnected CA3 pyramidal cell region.

scholarly journals IgSF11 homophilic adhesion proteins promote layer-specific synaptic assembly of the cortical interneuron subtype

2021 ◽  
Vol 7 (29) ◽  
pp. eabf1600
Author(s):  
Yasufumi Hayano ◽  
Yugo Ishino ◽  
Jung Ho Hyun ◽  
Carlos G. Orozco ◽  
André Steinecke ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Cell Types ◽  
Network Activity ◽  
Local Network ◽  
Immunoglobulin Superfamily ◽  
Specific Cell ◽  
Loss Of Function ◽  
Adhesion Proteins ◽  
Homophilic Adhesion

The most prominent structural hallmark of the mammalian neocortical circuitry is the layer-based organization of specific cell types and synaptic inputs. Accordingly, cortical inhibitory interneurons (INs), which shape local network activity, exhibit subtype-specific laminar specificity of synaptic outputs. However, the underlying molecular mechanisms remain unknown. Here, we demonstrate that Immunoglobulin Superfamily member 11 (IgSF11) homophilic adhesion proteins are preferentially expressed in one of the most distinctive IN subtypes, namely, chandelier cells (ChCs) that specifically innervate axon initial segments of pyramidal neurons (PNs), and their synaptic laminar target. Loss-of-function experiments in either ChCs or postsynaptic cells revealed that IgSF11 is required for ChC synaptic development in the target layer. While overexpression of IgSF11 in ChCs enlarges ChC presynaptic boutons, expressing IgSF11 in nontarget layers induces ectopic ChC synapses. These findings provide evidence that synapse-promoting adhesion proteins, highly localized to synaptic partners, determine the layer-specific synaptic connectivity of the cortical IN subtype.

scholarly journals Untangling stability and gain modulation in cortical circuits with multiple interneuron classes

2020 ◽  
Author(s):  
Hannah Bos ◽  
Anne-Marie Oswald ◽  
Brent Doiron
Keyword(s):  
Pyramidal Neurons ◽  
Mean Field ◽  
Gain Control ◽  
Cell Types ◽  
High Gain ◽  
Cortical Inhibition ◽  
Network Activity ◽  
Inhibitory Neurons ◽  
Neuron Models ◽  
Cortical Circuit

AbstractSynaptic inhibition is the mechanistic backbone of a suite of cortical functions, not the least of which is maintaining overall network stability as well as modulating neuronal gain. Past cortical models have assumed simplified recurrent networks in which all inhibitory neurons are lumped into a single effective pool. In such models the mechanics of inhibitory stabilization and gain control are tightly linked in opposition to one another – meaning high gain coincides with low stability and vice versa. This tethering of stability and response gain restricts the possible operative regimes of the network. However, it is now well known that cortical inhibition is very diverse, with molecularly distinguished cell classes having distinct positions within the cortical circuit. In this study, we analyze populations of spiking neuron models and associated mean-field theories capturing circuits with pyramidal neurons as well as parvalbumin (PV) and somatostatin (SOM) expressing interneurons. Our study outlines arguments for a division of labor within the full cortical circuit where PV interneurons are ideally positioned to stabilize network activity, whereas SOM interneurons serve to modulate pyramidal cell gain. This segregation of inhibitory function supports stable cortical dynamics over a large range of modulation states. Our study offers a blueprint for how to relate the circuit structure of cortical networks with diverse cell types to the underlying population dynamics and stimulus response.

scholarly journals Meta-Analysis of cortical inhibitory interneurons markers landscape and their performances in scRNA-seq studies.

2021 ◽  
Author(s):  
Lorenzo Martini ◽  
Roberta Bardini ◽  
Stefano Di Carlo
Keyword(s):  
Single Cell ◽  
Meta Analysis ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Marker Genes ◽  
Inhibitory Interneurons ◽  
Rna Seq ◽  
Circuit Function ◽  
The Brain

The mammalian cortex contains a great variety of neuronal cells. In particular, GABAergic interneurons, which play a major role in neuronal circuit function, exhibit an extraordinary diversity of cell types. In this regard, single-cell RNA-seq analysis is crucial to study cellular heterogeneity. To identify and analyze rare cell types, it is necessary to reliably label cells through known markers. In this way, all the related studies are dependent on the quality of the employed marker genes. Therefore, in this work, we investigate how a set of chosen inhibitory interneurons markers perform. The gene set consists of both immunohistochemistry-derived genes and single-cell RNA-seq taxonomy ones. We employed various human and mouse datasets of the brain cortex, consequently processed with the Monocle3 pipeline. We defined metrics based on the relations between unsupervised cluster results and the marker expression. Specifically, we calculated the specificity, the fraction of cells expressing, and some metrics derived from decision tree analysis like entropy gain and impurity reduction. The results highlighted the strong reliability of some markers but also the low quality of others. More interestingly, though, a correlation emerges between the general performances of the genes set and the experimental quality of the datasets. Therefore, the proposed method allows evaluating the quality of a dataset in relation to its reliability regarding the inhibitory interneurons cellular heterogeneity study.

Locomotor Rhythm Evoked by Ventrolateral Funiculus Stimulation in the Neonatal Rat Spinal Cord In Vitro

1997 ◽  
Vol 77 (1) ◽  
pp. 200-206 ◽  
Author(s):  
David S. K. Magnuson ◽  
Tammy C. Trinder
Keyword(s):  
Rhythmic Activity ◽  
Ventral Root ◽  
Neonatal Rat ◽  
Rat Spinal Cord ◽  
Locomotor Rhythm ◽  
Ventral Roots ◽  
Root Responses ◽  
Bilateral Projection ◽  
Ventrolateral Funiculus

Magnuson, David S. K. and Tammy C. Trinder. Locomotor rhythm evoked by ventrolateral funiculus stimulation in the neonatal rat spinal cord in vitro. J. Neurophysiol. 77: 200–206, 1997. Spinal cords from 2- to 8-day-old rats, maintained in vitro, were used to investigate the effects of discrete electrical stimuli applied to the ventrolateral funiculus (VLF) on motor neuron activity recorded from the lumbar ventral roots. Short trains of stimuli (1–3 s) delivered to one VLF in the low cervical region elicited rhythmic activity that persisted for up to 30 s. Responses consisted of short periods of activity (1–5 s) occurring simultaneously in the ipsilateral L5 and contralateral L3 ventral roots that alternated with similar bursts of activity in the ipsilateral L3 ventral root, a pattern consistent with locomotion. The rhythmicity of the ventral root responses to VLF stimulation was not affected by midsagittal sectioning of the preparation rostral to T10 and/or caudal to L4. Midsagittal sectioning of the lower thoracic or upper lumbar segments, however, disrupted the rhythmicity of the ventral root responses, leaving only long-duration simultaneous activation of the ipsilateral roots following VLF stimulus trains. The minimum lesion that effectively abolished the rhythmicity was one that divided only the L2 and L3 segments. In preparations rendered arrhythmic to VLF stimulation by an L2/L3 midsagittal lesion, rhythmicity could still be induced by N-methyl-d-aspartate (NMDA; 2–5 μM) and serotonin (5-HT; 20–50 μM), a drug combination commonly used to induce locomotor-like rhythmicity and air-stepping in vitro. Field potentials recorded following single stimuli delivered to the VLF revealed short-latency, large-amplitude responses in the ventral horn and intermediate gray both ipsilateral and contralateral to the stimulus site at T12 and L2. These observations suggest that 1) the discrete pathway under study may be an important descending locomotor command pathway and 2) this pathway has a strong bilateral projection in the lower thoracic and upper lumbar segments that is crucial for the initiation of VLF-induced rhythmic motor output. The induction of rhythmicity by NMDA/5-HT in an L2/L3-lesioned preparation suggests that these two rhythmogenic mechanisms may represent different levels within the circuitry that comprises the central pattern generator for locomotion. The rhythmic activity resulting from VLF stimulation is dependent on a bilateral projection that can be bypassed by the generalized excitation and subsequent rhythmicity that results from bath application of the NMDA/5-HT combination.

scholarly journals Impaired long-range synchronization of gamma oscillations in the neocortex of a mouse lacking Kv3.2 potassium channels

2012 ◽  
Vol 108 (3) ◽  
pp. 827-833 ◽  
Author(s):  
Michael Harvey ◽  
David Lau ◽  
Eugene Civillico ◽  
Bernardo Rudy ◽  
Diego Contreras
Keyword(s):  
Long Range ◽  
High Frequency ◽  
Single Cells ◽  
Critical Role ◽  
Pyramidal Cells ◽  
Gamma Oscillations ◽  
Network Activity ◽  
Inhibitory Interneurons ◽  
Phase Lag ◽  
Firing Properties

Inhibitory interneurons play a critical role in the generation of gamma (20–50 Hz) oscillations, either by forming mutually inhibitory networks or as part of recurrent networks with pyramidal cells. A key property of fast spiking interneurons is their ability to generate brief spikes and high-frequency spike trains with little accommodation. However, the role of their firing properties in network oscillations has not been tested in vivo. Studies in hippocampus in vitro have shown that high-frequency spike doublets in interneurons play a key role in the long-range synchronization of gamma oscillations with little phase lag despite long axonal conduction delays. We generated a knockout (KO) mouse lacking Kv3.2 potassium channel subunits, where infragranular inhibitory interneurons lose the ability both to sustain high-frequency firing and reliably generate high-frequency spike doublets. We recorded cortical local field potentials in anesthetized and awake, restrained mice. Spontaneous activity of the KO and the wild-type (WT) showed similar content of gamma and slow (0.1–15 Hz) frequencies, but the KO showed a significantly larger decay of synchronization of gamma oscillations with distance. Coronal cuts in the cortex of WT mice decreased synchronization to values similar to the intact KO. The synchronization of the slow oscillation showed little decay with distance in both mice and was largely reduced after coronal cuts. Our results show that the firing properties of inhibitory interneurons are critical for long-range synchronization of gamma oscillations, and emphasize that intrinsic electrophysiological properties of single cells may play a key role in the spatiotemporal characteristics of network activity.

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