scholarly journals Implications of Extended Inhibitory Neuron Development

2021 ◽  
Vol 22 (10) ◽  
pp. 5113
Author(s):  
Jae-Yeon Kim ◽  
Mercedes F. Paredes
Keyword(s):  
Neural Circuit ◽  
Inhibitory Neuron ◽  
Postnatal Period ◽  
Specific Pattern ◽  
Inhibitory Neurons ◽  
Gabaergic Interneuron ◽  
Gabaergic Interneurons ◽  
Neuron Development ◽  
Cortical Regions ◽  
Circuit Formation

A prolonged developmental timeline for GABA (γ-aminobutyric acid)-expressing inhibitory neurons (GABAergic interneurons) is an amplified trait in larger, gyrencephalic animals. In several species, the generation, migration, and maturation of interneurons take place over several months, in some cases persisting after birth. The late integration of GABAergic interneurons occurs in a region-specific pattern, especially during the early postnatal period. These changes can contribute to the formation of functional connectivity and plasticity, especially in the cortical regions responsible for higher cognitive tasks. In this review, we discuss GABAergic interneuron development in the late gestational and postnatal forebrain. We propose the protracted development of interneurons at each stage (neurogenesis, neuronal migration, and network integration), as a mechanism for increased complexity and cognitive flexibility in larger, gyrencephalic brains. This developmental feature of interneurons also provides an avenue for environmental influences to shape neural circuit formation.

scholarly journals GABAergic neuron-specific whole-brain transduction by AAV-PHP.B incorporated with a new GAD65 promoter

2021 ◽  
Author(s):  
Chiaki Hoshino ◽  
Ayumu Konno ◽  
Nobutake Hosoi ◽  
Ryosuke Kaneko ◽  
Ryo Mukai ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Fluorescent Protein ◽  
Critical Role ◽  
Inhibitory Neuron ◽  
Inhibitory Neurons ◽  
Acid Decarboxylase ◽  
Gabaergic Interneurons ◽  
Drug Induced ◽  
Whole Brain ◽  
Chandelier Cells

Abstract GABAergic interneurons play a critical role in tuning neural networks in the central nervous system, and their defects are associated with neuropsychiatric disorders. Currently, the mDlx enhancer is solely used for adeno-associated virus (AAV) vector-mediated transgene delivery into cortical interneurons. Here, we developed a new inhibitory neuron-specific promoter (designated as the mGAD65 promoter), with a length of 2.5 kb, from a mouse genome upstream of exon 1 of the Gad2 gene encoding glutamic acid decarboxylase (GAD) 65. Intravenous infusion of blood-brain barrier-penetrating AAV-PHP.B expressing an enhanced green fluorescent protein under the control of the mGAD65 promoter transduced the whole brain in an inhibitory neuron-specific manner. The specificity and efficiency of the mGAD65 promoter for GABAergic interneurons, which was assessed at the motor cortex, were almost identical to or slightly higher than those of the mDlx enhancer. Immunohistochemical analysis revealed that the mGAD65 promoter preferentially transduced parvalbumin (PV)-expressing interneurons. Notably, the mGAD65 promoter transduced chandelier cells more efficiently than the mDlx enhancer and robustly labeled their synaptic boutons, called the cartridge, targeting the axon initial segments of excitatory pyramidal neurons. To test the ability of the mGAD65 promoter to express a functional molecule, we virally expressed G-CaMP, a fluorescent Ca2+ indicator, in the motor cortex, and this enabled us to monitor spontaneous and drug-induced Ca2+ activity in GABAergic inhibitory neurons. These results suggest that the mGAD65 promoter is useful for AAV-mediated targeting and manipulation of GABAergic neurons with the dominance of cortical PV-expressing neurons, including chandelier cells.

scholarly journals GABAergic neuron-specific whole-brain transduction by AAV-PHP.B incorporated with a new GAD65 promoter

2021 ◽  
Author(s):  
Chiaki Hoshino ◽  
Ayumu Konno ◽  
Nobutake Hosoi ◽  
Ryosuke Kaneko ◽  
Ryo Mukai ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Fluorescent Protein ◽  
Critical Role ◽  
Inhibitory Neuron ◽  
Inhibitory Neurons ◽  
Acid Decarboxylase ◽  
Gabaergic Interneurons ◽  
Drug Induced ◽  
Whole Brain ◽  
Chandelier Cells

Abstract GABAergic interneurons play a critical role in tuning neural networks in the central nervous system, and their defects are associated with neuropsychiatric disorders. Currently, the mDlx enhancer is solely used for adeno-associated virus (AAV) vector-mediated transgene delivery into cortical interneurons. Here, we developed a new inhibitory neuron-specific promoter (designated as the mGAD65 promoter), with a length of 2.5 kb, from a mouse genome upstream of exon 1 of the Gad2 gene encoding glutamic acid decarboxylase (GAD) 65. Intravenous infusion of blood-brain barrier-penetrating AAV-PHP.B expressing an enhanced green fluorescent protein under the control of the mGAD65 promoter transduced the whole brain in an inhibitory neuron-specific manner. The specificity and efficiency of the mGAD65 promoter for GABAergic interneurons, which was assessed at the motor cortex, were almost identical to or slightly higher than those of the mDlx enhancer. Immunohistochemical analysis revealed that the mGAD65 promoter preferentially transduced parvalbumin (PV)-expressing interneurons. Notably, the mGAD65 promoter transduced chandelier cells more efficiently than the mDlx enhancer and robustly labeled their synaptic boutons, called the cartridge, targeting the axon initial segments of excitatory pyramidal neurons. To test the ability of the mGAD65 promoter to express a functional molecule, we virally expressed G-CaMP, a fluorescent Ca2+ indicator, in the motor cortex, and this enabled us to monitor spontaneous and drug-induced Ca2+ activity in GABAergic inhibitory neurons. These results suggest that the mGAD65 promoter is useful for AAV-mediated targeting and manipulation of GABAergic neurons with the dominance of cortical PV-expressing neurons, including chandelier cells.

scholarly journals Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner

2019 ◽  
Vol 25 (10) ◽  
pp. 2313-2329 ◽  
Author(s):  
Navneet A. Vasistha ◽  
Maria Pardo-Navarro ◽  
Janina Gasthaus ◽  
Dilys Weijers ◽  
Michaela K. Müller ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Selective Vulnerability ◽  
Gabaergic Interneuron ◽  
Gabaergic Interneurons ◽  
Affected Offspring ◽  
Cortical Interneuron ◽  
Inhibitory Circuits ◽  
Maternal Inflammation ◽  
Cortical Regions ◽  
Interneuron Development

Abstract Severe infections during pregnancy are one of the major risk factors for cognitive impairment in the offspring. It has been suggested that maternal inflammation leads to dysfunction of cortical GABAergic interneurons that in turn underlies cognitive impairment of the affected offspring. However, the evidence comes largely from studies of adult or mature brains and how the impairment of inhibitory circuits arises upon maternal inflammation is unknown. Here we show that maternal inflammation affects multiple steps of cortical GABAergic interneuron development, i.e., proliferation of precursor cells, migration and positioning of neuroblasts, as well as neuronal maturation. Importantly, the development of distinct subtypes of cortical GABAergic interneurons was discretely impaired as a result of maternal inflammation. This translated into a reduction in cell numbers, redistribution across cortical regions and layers, and changes in morphology and cellular properties. Furthermore, selective vulnerability of GABAergic interneuron subtypes was associated with the stage of brain development. Thus, we propose that maternally derived insults have developmental stage-dependent effects, which contribute to the complex etiology of cognitive impairment in the affected offspring.

scholarly journals Maternal inflammation has a profound effect on cortical interneuron development in a stage and subtype-specific manner

2018 ◽  
Author(s):  
Navneet A. Vasistha ◽  
Maria Pardo-Navarro ◽  
Janina Gasthaus ◽  
Dilys Weijers ◽  
Michaela K. Müller ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Selective Vulnerability ◽  
Gabaergic Interneuron ◽  
Gabaergic Interneurons ◽  
Affected Offspring ◽  
Inhibitory Circuits ◽  
Maternal Inflammation ◽  
Mature Brain ◽  
Cortical Regions ◽  
Interneuron Development

AbstractSevere infections during pregnancy are one of the major risk factors for cognitive brain impairment in offspring. It has been suggested that maternal inflammation leads to dysfunction of cortical GABAergic interneurons that in turn underlies cognitive impairment of the affected offspring. However, the evidence comes largely from studies of adult or mature brain and how impairment of inhibitory circuits arises upon maternal inflammation is unknown. Here we show that maternal inflammation affects multiple steps of cortical GABAergic interneuron development, i.e. proliferation of precursor cells, migration and positioning of neuroblasts as well as neuronal maturation. Importantly, the development of distinct subtypes of cortical GABAergic interneurons was discretely impaired as a result of maternal inflammation. This translated into a reduction in cell numbers, redistribution across cortical regions and layers, changes in morphology and cellular properties. Furthermore, selective vulnerability of GABAergic interneuron subtypes was associated with the stage of brain development. Thus, we propose that maternally-derived insults have developmental stage-dependent effects which contribute to the complex etiology of cognitive impairment in the affected offspring.

scholarly journals The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

2020 ◽  
Author(s):  
Candace H. Carriere ◽  
Anson D. Sing ◽  
Wendy Xueyi Wang ◽  
Brian E. Jones ◽  
Yohan Yee ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Inhibitory Neurons ◽  
Motor Deficits ◽  
Gabaergic Interneuron ◽  
Gabaergic Interneurons ◽  
Developmentally Regulated ◽  
Regulated Cell Death ◽  
Inhibitory Networks

SUMMARYInhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the cortex, the formation of inhibitory networks occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The molecular mechanisms that select GABAergic interneurons to survive or die are unknown. Here we report that the clustered Protocadherins regulate GABAergic cell survival in the developing brain. Deletion of the Pcdh-gamma genes (Pcdhgs) from GABAergic neurons in mice causes a severe loss of inhibitory neurons in multiple brain regions and results in motor deficits and seizure activities. By focusing on the neocortex and cerebellar cortex, we demonstrate that GABAergic interneuron loss results from elevated apoptosis during the postnatal wave of Bax-dependent programmed cell death. Pro-survival AKT signals are reduced in Pcdhg-deficient interneurons, diminishing the intrinsic capacity of interneurons to compete and incorporate into developing networks. We propose that the Pcdhgs mediate selective GABAergic interneuron survival to contribute to the formation of balanced inhibitory networks.

scholarly journals GABAergic neuron-specific whole-brain transduction by AAV-PHP.B incorporated with a new GAD65 promoter

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Chiaki Hoshino ◽  
Ayumu Konno ◽  
Nobutake Hosoi ◽  
Ryosuke Kaneko ◽  
Ryo Mukai ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Fluorescent Protein ◽  
Critical Role ◽  
Inhibitory Neuron ◽  
Inhibitory Neurons ◽  
Acid Decarboxylase ◽  
Gabaergic Interneurons ◽  
Drug Induced ◽  
Whole Brain ◽  
Chandelier Cells

AbstractGABAergic interneurons play a critical role in tuning neural networks in the central nervous system, and their defects are associated with neuropsychiatric disorders. Currently, the mDlx enhancer is solely used for adeno-associated virus (AAV) vector-mediated transgene delivery into cortical interneurons. Here, we developed a new inhibitory neuron-specific promoter (designated as the mGAD65 promoter), with a length of 2.5 kb, from a mouse genome upstream of exon 1 of the Gad2 gene encoding glutamic acid decarboxylase (GAD) 65. Intravenous infusion of blood–brain barrier-penetrating AAV-PHP.B expressing an enhanced green fluorescent protein under the control of the mGAD65 promoter transduced the whole brain in an inhibitory neuron-specific manner. The specificity and efficiency of the mGAD65 promoter for GABAergic interneurons, which was assessed at the motor cortex, were almost identical to or slightly higher than those of the mDlx enhancer. Immunohistochemical analysis revealed that the mGAD65 promoter preferentially transduced parvalbumin (PV)-expressing interneurons. Notably, the mGAD65 promoter transduced chandelier cells more efficiently than the mDlx enhancer and robustly labeled their synaptic boutons, called the cartridge, targeting the axon initial segments of excitatory pyramidal neurons. To test the ability of the mGAD65 promoter to express a functional molecule, we virally expressed G-CaMP, a fluorescent Ca2+ indicator, in the motor cortex, and this enabled us to monitor spontaneous and drug-induced Ca2+ activity in GABAergic inhibitory neurons. These results suggest that the mGAD65 promoter is useful for AAV-mediated targeting and manipulation of GABAergic neurons with the dominance of cortical PV-expressing neurons, including chandelier cells.

Endocannabinoid system in the neurodevelopment of GABAergic interneurons: implications for neurological and psychiatric disorders

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Chang-geng Song ◽  
Xin Kang ◽  
Fang Yang ◽  
Wan-qing Du ◽  
Jia-jia Zhang ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Network Activity ◽  
Inhibitory Neurons ◽  
Gabaergic Interneurons ◽  
Neural Stem Progenitor Cells ◽  
The Central Nervous System ◽  
Interneuron Development

Abstract In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.

scholarly journals Amyloid-β Oligomers Induce Only Mild Changes to Inhibitory Bouton Dynamics

2021 ◽  
Vol 5 (1) ◽  
pp. 153-160 ◽  
Author(s):  
Marvin Ruiter ◽  
Christine Lützkendorf ◽  
Jian Liang ◽  
Corette J. Wierenga
Keyword(s):  
Hippocampal Slices ◽  
Inhibitory Neuron ◽  
Amyloid Β ◽  
Inhibitory Neurons ◽  
Inhibitory Synapses ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein ◽  
Plaque Load ◽  
Early Alzheimer’S Disease

The amyloid-β protein precursor is highly expressed in a subset of inhibitory neuron in the hippocampus, and inhibitory neurons have been suggested to play an important role in early Alzheimer’s disease plaque load. Here we investigated bouton dynamics in axons of hippocampal interneurons in two independent amyloidosis models. Short-term (24 h) amyloid-β (Aβ)-oligomer application to organotypic hippocampal slices slightly increased inhibitory bouton dynamics, but bouton density and dynamics were unchanged in hippocampus slices of young-adult AppNL - F - G-mice, in which Aβ levels are chronically elevated. These results indicate that loss or defective adaptation of inhibitory synapses are not a major contribution to Aβ-induced hyperexcitability.

scholarly journals Aberrant development of excitatory circuits to inhibitory neurons in the primary visual cortex after neonatal binocular enucleation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rongkang Deng ◽  
Joseph P. Y. Kao ◽  
Patrick O. Kanold
Keyword(s):  
Visual Cortex ◽  
Nmda Receptors ◽  
Laser Scanning ◽  
Inhibitory Neurons ◽  
Gabaergic Interneurons ◽  
Cortical Circuits ◽  
Retinal Input ◽  
Layer 4 ◽  
Ampa And Nmda Receptors ◽  
Laser Scanning Photostimulation

AbstractThe development of GABAergic interneurons is important for the functional maturation of cortical circuits. After migrating into the cortex, GABAergic interneurons start to receive glutamatergic connections from cortical excitatory neurons and thus gradually become integrated into cortical circuits. These glutamatergic connections are mediated by glutamate receptors including AMPA and NMDA receptors and the ratio of AMPA to NMDA receptors decreases during development. Since previous studies have shown that retinal input can regulate the early development of connections along the visual pathway, we investigated if the maturation of glutamatergic inputs to GABAergic interneurons in the visual cortex requires retinal input. We mapped the spatial pattern of glutamatergic connections to layer 4 (L4) GABAergic interneurons in mouse visual cortex at around postnatal day (P) 16 by laser-scanning photostimulation and investigated the effect of binocular enucleations at P1/P2 on these patterns. Gad2-positive interneurons in enucleated animals showed an increased fraction of AMPAR-mediated input from L2/3 and a decreased fraction of input from L5/6. Parvalbumin-expressing (PV) interneurons showed similar changes in relative connectivity. NMDAR-only input was largely unchanged by enucleation. Our results show that retinal input sculpts the integration of interneurons into V1 circuits and suggest that the development of AMPAR- and NMDAR-only connections might be regulated differently.

Optical survey of neural circuit formation in the embryonic chick vagal pathway

2004 ◽  
Vol 19 (5) ◽  
pp. 1217-1225 ◽  
Author(s):  
Katsushige Sato ◽  
Naohisa Miyakawa ◽  
Yoko Momose-Sato
Keyword(s):  
Neural Circuit ◽  
Embryonic Chick ◽  
Vagal Pathway ◽  
Circuit Formation
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