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Trends in Neurosciences Aug 2020Chandelier cells (ChCs) are a unique type of GABAergic interneuron that selectively innervate the axon initial segment (AIS) of excitatory pyramidal neurons; the... (Review)
Review
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).
Topics: Adult; Autism Spectrum Disorder; Humans; Interneurons; Neocortex; Neurons; Pyramidal Cells
PubMed: 32564887
DOI: 10.1016/j.tins.2020.05.003 -
ENeuro May 2024Canonically, action potentials of most mammalian neurons initiate at the axon initial segment (AIS) and propagate bidirectionally: orthodromically along the distal axon...
Canonically, action potentials of most mammalian neurons initiate at the axon initial segment (AIS) and propagate bidirectionally: orthodromically along the distal axon and retrogradely into the soma and dendrites. Under some circumstances, action potentials may initiate ectopically, at sites distal to the AIS, and propagate antidromically along the axon. These "ectopic action potentials" (EAPs) have been observed in experimental models of seizures and chronic pain, and more rarely in nonpathological forebrain neurons. Here we report that a large majority of parvalbumin-expressing (PV+) interneurons in the upper layers of mouse neocortex, from both orbitofrontal and primary somatosensory areas, fire EAPs after sufficient activation of their somata. Somatostatin-expressing interneurons also fire EAPs, though less robustly. Ectopic firing in PV+ cells occurs in varying temporal patterns and can persist for several seconds. PV+ cells evoke strong synaptic inhibition in pyramidal neurons and interneurons and play critical roles in cortical function. Our results suggest that ectopic spiking of PV+ interneurons is common and may contribute to both normal and pathological network functions of the neocortex.
Topics: Animals; Parvalbumins; Interneurons; Neocortex; Action Potentials; Mice, Transgenic; Male; Mice; Female; Mice, Inbred C57BL; Pyramidal Cells; Somatostatin
PubMed: 38637152
DOI: 10.1523/ENEURO.0314-23.2024 -
Anatomical Science International Jul 2023Morphological analysis of organelles is one of the important clues for understanding the cellular conditions and mechanisms occurring in cells. In particular, nanoscale... (Review)
Review
Morphological analysis of organelles is one of the important clues for understanding the cellular conditions and mechanisms occurring in cells. In particular, nanoscale information within crowded intracellular organelles of tissues provide more direct implications when compared to analyses of cells in culture or isolation. However, there are some difficulties in detecting individual shape using light microscopy, including super-resolution microscopy. Transmission electron microscopy (TEM), wherein the ultrastructure can be imaged at the membrane level, cannot determine the whole structure, and analyze it quantitatively. Volume EM, such as focused ion beam/scanning electron microscopy (FIB/SEM), can be a powerful tool to explore the details of three-dimensional ultrastructures even within a certain volume, and to measure several parameters from them. In this review, the advantages of FIB/SEM analysis in organelle studies are highlighted along with the introduction of mitochondrial analysis in injured motor neurons. This would aid in understanding the morphological details of mitochondria, especially those distributed in the cell bodies as well as in the axon initial segment (AIS) in mouse tissues. These regions have not been explored thus far due to the difficulties encountered in accessing their images by conditional microscopies. Some mechanisms of nerve regeneration have also been discussed with reference to the obtained findings. Finally, future perspectives on FIB/SEM are introduced. The combination of biochemical and genetic understanding of organelle structures and a nanoscale understanding of their three-dimensional distribution and morphology will help to match achievements in genomics and structural biology.
Topics: Mice; Animals; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Motor Neurons; Volume Electron Microscopy; Organelles; Imaging, Three-Dimensional
PubMed: 37071350
DOI: 10.1007/s12565-023-00720-y -
Nature Communications Jun 2022Understanding how diverse neurons are assembled into circuits requires a framework for describing cell types and their developmental trajectories. Here we combine...
Understanding how diverse neurons are assembled into circuits requires a framework for describing cell types and their developmental trajectories. Here we combine genetic fate-mapping, pseudotemporal profiling of morphogenesis, and dual morphology and RNA labeling to resolve the diversification of mouse cerebellar inhibitory interneurons. Molecular layer interneurons (MLIs) derive from a common progenitor population but comprise diverse dendritic-, somatic-, and axon initial segment-targeting interneurons. Using quantitative morphology from 79 mature MLIs, we identify two discrete morphological types and presence of extensive within-class heterogeneity. Pseudotime trajectory inference using 732 developmental morphologies indicate the emergence of distinct MLI types during migration, before reaching their final positions. By comparing MLI identities from morphological and transcriptomic signatures, we demonstrate the dissociation between these modalities and that subtype divergence can be resolved from axonal morphogenesis prior to marker gene expression. Our study illustrates the utility of applying single-cell methods to quantify morphology for defining neuronal diversification.
Topics: Animals; Cerebellum; Interneurons; Mice; Neurons
PubMed: 35701402
DOI: 10.1038/s41467-022-30977-2 -
Aging Cell Jun 2021Serotonin 6 receptor (5-HT6R) is a promising target for a variety of human diseases, such as Alzheimer's disease (AD) and schizophrenia. However, the detailed mechanism...
Serotonin 6 receptor (5-HT6R) is a promising target for a variety of human diseases, such as Alzheimer's disease (AD) and schizophrenia. However, the detailed mechanism underlying 5-HT6R activity in the central nervous system (CNS) is not fully understood. In the present study, 5-HT6R null mutant (5-HT6R ) mice were found to exhibit cognitive deficiencies and abnormal anxiety levels. 5-HT6R is considered to be specifically localized on the primary cilia. We found that the loss of 5-HT6R affected the Sonic Hedgehog signaling pathway in the primary cilia. 5-HT6R mice showed remarkable alterations in neuronal morphology, including dendrite complexity and axon initial segment morphology. Neurons lacking 5-HT6R exhibited increased neuronal excitability. Our findings highlight the complexity of 5-HT6R functions in the primary ciliary and neuronal physiology, supporting the theory that this receptor modulates neuronal morphology and transmission, and contributes to cognitive deficits in a variety of human diseases, such as AD, schizophrenia, and ciliopathies.
Topics: Alzheimer Disease; Animals; Cognitive Dysfunction; Disease Models, Animal; Mice; Mice, Inbred C57BL; Receptors, Serotonin; Synapses
PubMed: 33960602
DOI: 10.1111/acel.13369 -
The Neuroscientist : a Review Journal... Apr 2024Repetitive transcranial magnetic stimulation (rTMS) has become an increasingly popular tool to modulate neural excitability and induce neural plasticity in clinical and... (Review)
Review
Repetitive transcranial magnetic stimulation (rTMS) has become an increasingly popular tool to modulate neural excitability and induce neural plasticity in clinical and preclinical models; however, the physiological mechanisms in which it exerts these effects remain largely unknown. To date, studies have primarily focused on characterizing rTMS-induced changes occurring at the synapse, with little attention given to changes in intrinsic membrane properties. However, accumulating evidence suggests that rTMS may induce its effects, in part, via intrinsic plasticity mechanisms, suggesting a new and potentially complementary understanding of how rTMS alters neural excitability and neural plasticity. In this review, we provide an overview of several intrinsic plasticity mechanisms before reviewing the evidence for rTMS-induced intrinsic plasticity. In addition, we discuss a select number of neurological conditions where rTMS-induced intrinsic plasticity has therapeutic potential before speculating on the temporal relationship between rTMS-induced intrinsic and synaptic plasticity.
Topics: Humans; Transcranial Magnetic Stimulation; Synapses; Neuronal Plasticity
PubMed: 36059273
DOI: 10.1177/10738584221118262 -
BioRxiv : the Preprint Server For... Mar 2024Axo-axonic cells (AACs), also called chandelier cells (ChCs) in the cerebral cortex, are the most distinctive type of GABAergic interneurons described in the neocortex,...
Axo-axonic cells (AACs), also called chandelier cells (ChCs) in the cerebral cortex, are the most distinctive type of GABAergic interneurons described in the neocortex, hippocampus, and basolateral amygdala (BLA). AACs selectively innervate glutamatergic projection neurons (PNs) at their axon initial segment (AIS), thus may exert decisive control over PN spiking and regulate PN functional ensembles. However, the brain-wide distribution, synaptic connectivity, and circuit function of AACs remains poorly understood, largely due to the lack of specific and reliable experimental tools. Here, we have established an intersectional genetic strategy that achieves specific and comprehensive targeting of AACs throughout the mouse brain based on their lineage () and molecular () markers. We discovered that AACs are deployed across essentially all the pallium-derived brain structures, including not only the dorsal pallium-derived neocortex and medial pallium-derived hippocampal formation, but also the lateral pallium-derived claustrum-insular complex, and the ventral pallium-derived extended amygdaloid complex and olfactory centers. AACs are also abundant in anterior olfactory nucleus, taenia tecta and lateral septum. AACs show characteristic variations in density across neocortical areas and layers and across subregions of the hippocampal formation. Neocortical AACs comprise multiple laminar subtypes with distinct dendritic and axonal arborization patterns. Retrograde monosynaptic tracing from AACs across neocortical, hippocampal and BLA regions reveal shared as well as distinct patterns of synaptic input. Specific and comprehensive targeting of AACs facilitates the study of their developmental genetic program and circuit function across brain structures, providing a ground truth platform for understanding the conservation and variation of a bona fide cell type across brain regions and species.
PubMed: 37986757
DOI: 10.1101/2023.11.07.566059 -
Frontiers in Cellular Neuroscience 2022Various cortical functions arise from the dynamic interplay of excitation and inhibition. GABAergic interneurons that mediate synaptic inhibition display significant...
Various cortical functions arise from the dynamic interplay of excitation and inhibition. GABAergic interneurons that mediate synaptic inhibition display significant diversity in cell morphology, electrophysiology, plasticity rule, and connectivity. These heterogeneous features are thought to underlie their functional diversity. Emerging attention on specific properties of the various interneuron types has emphasized the crucial role of cell-type specific inhibition in cortical neural processing. However, knowledge is still limited on how each interneuron type forms distinct neural circuits and regulates network activity in health and disease. To dissect interneuron heterogeneity at single cell-type precision, we focus on the chandelier cell (ChC), one of the most distinctive GABAergic interneuron types that exclusively innervate the axon initial segments (AIS) of excitatory pyramidal neurons. Here we review the current understanding of the structural and functional properties of ChCs and their implications in behavioral functions, network activity, and psychiatric disorders. These findings provide insights into the distinctive roles of various single-type interneurons in cortical neural coding and the pathophysiology of cortical dysfunction.
PubMed: 36299494
DOI: 10.3389/fncel.2022.992409 -
Neuron Oct 2019The axon initial segment (AIS) is a unique neuronal compartment that plays a crucial role in the generation of action potential and neuronal polarity. The assembly of...
The axon initial segment (AIS) is a unique neuronal compartment that plays a crucial role in the generation of action potential and neuronal polarity. The assembly of the AIS requires membrane, scaffolding, and cytoskeletal proteins, including Ankyrin-G and TRIM46. How these components cooperate in AIS formation is currently poorly understood. Here, we show that Ankyrin-G acts as a scaffold interacting with End-Binding (EB) proteins and membrane proteins such as Neurofascin-186 to recruit TRIM46-positive microtubules to the plasma membrane. Using in vitro reconstitution and cellular assays, we demonstrate that TRIM46 forms parallel microtubule bundles and stabilizes them by acting as a rescue factor. TRIM46-labeled microtubules drive retrograde transport of Neurofascin-186 to the proximal axon, where Ankyrin-G prevents its endocytosis, resulting in stable accumulation of Neurofascin-186 at the AIS. Neurofascin-186 enrichment in turn reinforces membrane anchoring of Ankyrin-G and subsequent recruitment of TRIM46-decorated microtubules. Our study reveals feedback-based mechanisms driving AIS assembly.
Topics: Animals; Ankyrins; Axon Initial Segment; Axonal Transport; COS Cells; Cell Adhesion Molecules; Cell Line, Tumor; Chlorocebus aethiops; Cytoskeleton; Endocytosis; Feedback, Physiological; HEK293 Cells; Hippocampus; Humans; Microtubule-Associated Proteins; Microtubules; Nerve Growth Factors; Neurons; Rats; Tripartite Motif Proteins
PubMed: 31474508
DOI: 10.1016/j.neuron.2019.07.029 -
Zoological Research Jul 2022Action potentials (APs) in neurons are generated at the axon initial segment (AIS). AP dynamics, including initiation and propagation, are intimately associated with...
Action potentials (APs) in neurons are generated at the axon initial segment (AIS). AP dynamics, including initiation and propagation, are intimately associated with neuronal excitability and neurotransmitter release kinetics. Most learning and memory studies at the single-neuron level have relied on the use of animal models, most notably rodents. Here, we studied AP initiation and propagation in cultured hippocampal neurons from Sprague-Dawley (SD) rats and C57BL/6 (C57) mice with genetically encoded voltage indicator (GEVI)-based voltage imaging. Our data showed that APs traveled bidirectionally in neurons from both species; forward-propagating APs (fpAPs) had a different speed than backpropagating APs (bpAPs). Additionally, we observed distinct AP propagation characteristics in AISs emerging from the somatic envelope compared to those originating from dendrites. Compared with rat neurons, mouse neurons exhibited higher bpAP speed and lower fpAP speed, more distally located ankyrin G (AnkG) in AISs, and longer Nav1.2 lengths in AISs. Moreover, during AIS plasticity, AnkG and Nav1.2 showed distal shifts in location and shorter lengths of labeled AISs in rat neurons; in mouse neurons, however, they showed a longer AnkG-labeled length and more distal Nav1.2 location. Our findings suggest that hippocampal neurons in SD rats and C57 mice may have different AP propagation speeds, different AnkG and Nav1.2 patterns in the AIS, and different AIS plasticity properties, indicating that comparisons between these species must be carefully considered.
Topics: Action Potentials; Animals; Axon Initial Segment; Axons; Mice; Mice, Inbred C57BL; Neurons; Rats; Rats, Sprague-Dawley
PubMed: 35758537
DOI: 10.24272/j.issn.2095-8137.2022.121