Axon terminals of GABAergic chandelier cells are lost at epileptic foci

doi:10.1016/0006-8993(85)90034-4

Brain Research

Volume 326, Issue 2, 11 February 1985, Pages 251-260

https://doi.org/10.1016/0006-8993(85)90034-4 Get rights and content

Abstract

Axon terminals of chandelier cells were analyzed in monkeys with cortical focal epilepsy produced by alumina gel to determine if this type of GABAergic terminal is lost at epileptic foci. These terminals form a dense plexus with the axon initial segments of pyramidal neurons, especially those in layers II and III. Axon initial segments of pyramidal neurons were traced for at least 40 μm in serial thin sections and beyond this point were observed to become myelinated. In single sections, 10–15 axon terminals were found to form symmetric synapses throughout the entire lenght of the axon initial segments from nonepileptic preparations and were observed to synapse with only these structures and not adjacent dendrites or spines. In epileptic cortex, the axon initial segments of pyramidal neurons were apposed by glial profiles that contained clusters of filaments typical of reactive astrocytes. Only a few, small axon terminals were observed to form symmetric synapses with these axon initial segments. Thus, the chandelier cell axons appeared to degenerate in epileptic cortex. The highly strategic site of GABAergic inhibitory synapses on axon initial segments suggests that they exert a strong influence on the output of pyramidal cells. The near absence of these chandelier cell axons in epileptic foci most likely contributes to the hyperexcitability of neurons.

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Uncovering the wiring rules employed by neurons during development represents a formidable challenge with important repercussions for neurodevelopmental disorders. Chandelier cells (ChCs) are a singular GABAergic interneuron type, with a unique morphology, that have recently begun to shed light on the rules that drive the formation and plasticity of inhibitory synapses. This review will focus on the wealth of recent data charting the emergence of synapses formed by ChCs onto pyramidal cells, from the molecules involved to the plasticity of these connections during development.
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For instance, altered regulation of PC firing activity has been found in movement disorders as well as cognitive dysfunction, including autism spectrum disorder (ASD) [45]. ChC connectivity defects have also been tied to ASD, in addition to schizophrenia and epilepsy, likely due to imbalances in E/I homeostasis [46–49]. Lastly, in the spinal cord, deficits in presynaptic inhibition of sensory neurons by GABApre terminals have been observed in individuals with Huntington and Parkinson diseases [50].
One of the most intriguing features of inhibitory synapses is the precision by which they innervate their target, not only at the cellular level but also at the subcellular level (i.e. axo-dendritic, axo-somatic, or axo-axonic innervation). In particular, in the cerebellum, cortex, and spinal cord, distinct and highly specialized GABAergic interneurons, such as basket cells, chandelier cells, and GABApre interneurons, form precise axo-axonic synapses, allowing them to directly regulate neuronal output and circuit function. In this article, we summarize our latest knowledge of the cellular and molecular mechanisms that regulate the establishment and maintenance of axo-axonic synapses in these regions of the CNS. We also detail the key roles of the L1CAM family of cell adhesion molecules in such GABAergic subcellular target recognition.
Etiology-related Degree of Sprouting of Parvalbumin-immunoreactive Axons in the Human Dentate Gyrus in Temporal Lobe Epilepsy
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Data are abundant about the sprouting of granule cell axons (mossy fibers) into the molecular layer of the DG. While mossy fibers normally terminate on both excitatory and inhibitory neurons of the CA3 region and those of the dentate hilus (Frotscher, 1985, 1989; Ribak, 1985; Claiborne et al., 1986; Soriano and Frotscher, 1993; Acsády et al., 1998), in the epileptic human hippocampal formation as well as in animal models of TLE, mossy terminals form synapses on granule cell dendrites in the molecular layer of the DG (Houser et al., 1990; Cavazos et al., 1991; Represa et al., 1993; Mathern et al., 1994; Franck et al., 1995). Sprouting of pyramidal cells’ axons in the CA1 region may result in a stronger excitatory input to neighboring pyramidal neurons (Lehmann et al., 2000, 2001).
In the present study, we examined parvalbumin-immunoreactive cells and axons in the dentate gyrus of surgically resected tissues of therapy-resistant temporal lobe epilepsy (TLE) patients with different etiologies. Based on MRI results, five groups of patients were formed: (1) hippocampal sclerosis (HS), (2) malformation of cortical development, (3) malformation of cortical development + HS, (4) tumor-induced TLE, (5) patients with negative MRI result. Four control samples were also included in the study. Parvalbumin-immunoreactive cells were observed mostly in subgranular location in the dentate hilus in controls, in tumor-induced TLE, in malformation of cortical development and in MR-negative cases. In patients with HS, significant decrease in the number of hilar parvalbumin-immunoreactive cells and large numbers of ectopic parvalbumin-containing neurons were detected in the dentate gyrus’ molecular layer. The ratio of ectopic/normally-located cells was significantly higher in HS than in other TLE groups. In patients with HS, robust sprouting of parvalbumin-immunoreactive axons were frequently visible in the molecular layer. The extent of sprouting was significantly higher in TLE patients with HS than in other groups. Strong sprouting of parvalbumin-immunoreactive axons were frequently observed in patients who had childhood febrile seizure. Significant correlation was found between the level of sprouting of axons and the ratio of ectopic/normally-located parvalbumin-containing cells. Electron microscopy demonstrated that sprouted parvalbumin-immunoreactive axons terminate on proximal and distal dendritic shafts as well as on dendritic spines of granule cells. Our results indicate alteration of target profile of parvalbumin-immunoreactive neurons in HS that contributes to the known synaptic remodeling in TLE.
Shedding Light on Chandelier Cell Development, Connectivity, and Contribution to Neural Disorders
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Chandelier cells (ChCs) are a unique type of GABAergic interneuron that selectively innervate the axon initial segment (AIS) of excitatory pyramidal neurons; the subcellular domain where action potentials are initiated. The proper genesis and maturation of ChCs is critical for regulating neural ensemble firing in the neocortex throughout development and adulthood. Recently, genetic and molecular studies have shed new light on the complex innerworkings of ChCs in health and disease. This review presents an overview of recent studies on the developmental origins, migratory properties, and morphology of ChCs. In addition, attention is given to newly identified molecules regulating ChC morphogenesis and connectivity as well as recent work linking ChC dysfunction to neural disorders, including schizophrenia, epilepsy, and autism spectrum disorder (ASD).
Axo-axonic Innervation of Neocortical Pyramidal Neurons by GABAergic Chandelier Cells Requires AnkyrinG-Associated L1CAM
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The striking selectivity of ChC innervation at the AIS of PyNs has intrigued neuroscientists ever since the initial discovery of ChCs in the 1970s (Jones, 1975; Somogyi, 1977; Szentágothai and Arbib, 1974). This interest has heightened with accruing evidence showing that this unique form of subcellular innervation allows ChCs to exert powerful yet precise control over cortical PyN spiking and population output (Howard et al., 2005; Inan and Anderson, 2014; Lu et al., 2017) and, in particular, given increasing reports linking ChC connectivity defects to neurological conditions, such as schizophrenia and epilepsy (Ariza et al., 2018; Del Pino et al., 2013; Lewis, 2011; Ribak, 1985; Rocco et al., 2017). Despite these findings, little to nothing is known about the mechanisms underlying the subcellular innervation of neocortical PyN AISs by ChCs.
Among the diverse interneuron subtypes in the neocortex, chandelier cells (ChCs) are the only population that selectively innervate pyramidal neurons (PyNs) at their axon initial segment (AIS), the site of action potential initiation, allowing them to exert powerful control over PyN output. Yet, mechanisms underlying their subcellular innervation of PyN AISs are unknown. To identify molecular determinants of ChC/PyN AIS innervation, we performed an in vivo RNAi screen of PyN-expressed axonal cell adhesion molecules (CAMs) and select Ephs/ephrins. Strikingly, we found the L1 family member L1CAM to be the only molecule required for ChC/PyN AIS innervation. Further, we show that L1CAM is required during both the establishment and maintenance of innervation, and that selective innervation of PyN AISs by ChCs requires AIS anchoring of L1CAM by the cytoskeletal ankyrin-G/βIV-spectrin complex. Thus, our findings identify PyN-expressed L1CAM as a critical CAM required for innervation of neocortical PyN AISs by ChCs.

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Research reportAxon terminals of GABAergic chandelier cells are lost at epileptic foci

Abstract

Neurotransmitter, receptor and biochemical changes in monkey cortical epileptic foci

Brain Research

GABA-mediated inhibition in the epileptogenic focus, a process which may be involved in the mechanism of cobalt induced epilepsy

Brain Research

Structural substrates of seizure foci in the human temporal lobe

Neuronal, dendritic and vascular profiles of human temporal lobe epilepsy correlated with cellular studies in vivo

Anatomical chemistry of the cerebral cortex

A specialized type of neuron in the visual cortex of cat. A Golgi and electron microscopic study of chandelier cells

J. comp. Neurol.

Electron microscopic alterations in the vicinity of epileptogenic cobalt-gelatine necrosis in the cerebral cortex of the rat

Acta Neuropathol.

Glutamate decarboxylase-immunoreactive terminals of Golgi-impregnated axoaxonic cells and of presumed basket cells in synaptic contact with pyramidal neurons of the cat's visual cortex

J. comp. Neurol.

Degeneration in experimental epileptic foci

Arch. Neurol.

Cortical neuroglia in experimental epilepsy

Exp. Neurol.

Synaptic organization of immunocytochemically identified GABA neurons in the monkey sensory-motor cortex

J. Neurocytol.

Morphological diversity of immunocytochemically identified GABA neurons in the monkey sensory-motor cortex

J. Neurocytol.

Anatomy of cerebral cortex: columnar input-output organization

Chemical nature of synaptic transmission in vertebrates

Physiol. Rev.

GABA-mediated inhibitory mechanisms in relation to epileptic discharges

Biochemical evidence for the alterations of GABA-mediated synaptic transmission in human epileptic foci

Epilepsy and γ-aminobutyric acid-mediated inhibition

Int. Rev. Neurobiol.

Research report
Axon terminals of GABAergic chandelier cells are lost at epileptic foci