GABAergic cell loss in mice lacking autism-associated geneSema6A

2019 ◽  
Author(s):  
Karlie Menzel ◽  
Gábor Szabó ◽  
Yuchio Yanagawa ◽  
Turhan Cocksaygan ◽  
Céline Plachez
Keyword(s):  
Brain Development ◽  
Neuronal Networks ◽  
Cell Loss ◽  
Cell Number ◽  
Autism Spectrum ◽  
Mutant Mice ◽  
Gabaergic Interneuron ◽  
Gabaergic Interneurons ◽  
Neuronal Connectivity ◽  
Histological Techniques

AbstractBackgroundDuring brain development, a multitude of neuronal networks form as neurons find their correct position within the brain and send out axons to synapse onto specific targets. Altered neuronal connectivity within these complex networks has been reported in Autism Spectrum Disorder (ASD), leading to alterations in brain function and multisensory integration. Semaphorins (also referred to as Semas), a large protein family of about 30 members, have been shown to play an important role in neuronal circuit formation and have been implicated in the etiology of ASD. The purpose of the current study is to investigate howSema6Amutation affects neuronal connectivity in ASD. SinceSema6Ais involved in cell migration, we hypothesized that during brain development the migration of GABAergic interneurons is affected by the loss ofSema6Agene, leading to alterations in Excitatory/Inhibitory (E/I) balance.MethodsSema6Atransgenic mice were crossed with either GAD65-GFP mice or GAD67-GFP mice to allow for both a reliable and robust staining of the GABAergic interneuron population within theSema6Amouse line. Using histological techniques we studies the expression of interneurons subtypes in the Sema6A mutant mice.ResultsAnalysis ofSema6Amutant mice crossed with either GAD65-GFP or GAD67-GFP knock-in mice revealed a reduced number of GABAergic interneurons in the primary somatosensory cortex, hippocampus, and reticular thalamic nucleus (RTN) in adultSema6Amutant mice. This reduction in cell number appeared to be targeted to the Parvalbumin (PV) interneuron cell population since neither the Calretinin nor the Calbindin expressing interneurons were affected by theSema6Amutation.LimitationsAlthough the use of animal models has been crucial for understanding the biological basis of autism, the complexity of the human brain can never truly be replicated by these models.ConclusionsTaken together, these findings suggest thatSema6Agene loss affects only the fast spiking-PV population and reveal the importance of an axon guidance molecule in the formation of GABAergic neuronal networks and provide insight into the molecular pathways that may lead to altered neuronal connectivity and E/I imbalance in ASD.

scholarly journals Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

2021 ◽  
Author(s):  
Megha Amar ◽  
Akula Bala Pramod ◽  
Nam-Kyung Yu ◽  
Victor Munive Herrera ◽  
Lily R. Qiu ◽  
...  
Keyword(s):  
Brain Development ◽  
Brain Mri ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Small Gtpase ◽  
Adult Brain ◽  
Mutant Mice ◽  
Network Activity ◽  
Proteomic Profiling ◽  
Filamentous Actin

AbstractE3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.

scholarly journals Altered Expression of GABAergic Markers in the Forebrain of Young and Adult Engrailed-2 Knockout Mice

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 384
Author(s):  
Giovanni Provenzano ◽  
Angela Gilardoni ◽  
Marika Maggia ◽  
Mattia Pernigo ◽  
Paola Sgadò ◽  
...  
Keyword(s):  
Gaba Receptors ◽  
Gaba Receptor ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Gabaergic Interneuron ◽  
Gabaergic Interneurons ◽  
Rt Pcr ◽  
Altered Expression ◽  
Gabaergic Neurotransmission ◽  
Adult Mice

Impaired function of GABAergic interneurons, and the subsequent alteration of excitation/inhibition balance, is thought to contribute to autism spectrum disorders (ASD). Altered numbers of GABAergic interneurons and reduced expression of GABA receptors has been detected in the brain of ASD subjects and mouse models of ASD. We previously showed a reduced expression of GABAergic interneuron markers parvalbumin (PV) and somatostatin (SST) in the forebrain of adult mice lacking the Engrailed2 gene (En2-/- mice). Here, we extended this analysis to postnatal day (P) 30 by using in situ hybridization, immunohistochemistry, and quantitative RT-PCR to study the expression of GABAergic interneuron markers in the hippocampus and somatosensory cortex of En2-/- and wild type (WT) mice. In addition, GABA receptor subunit mRNA expression was investigated by quantitative RT-PCR in the same brain regions of P30 and adult En2-/- and WT mice. As observed in adult animals, PV and SST expression was decreased in En2-/- forebrain of P30 mice. The expression of GABA receptor subunits (including the ASD-relevant Gabrb3) was also altered in young and adult En2-/- forebrain. Our results suggest that GABAergic neurotransmission deficits are already evident at P30, confirming that neurodevelopmental defects of GABAergic interneurons occur in the En2 mouse model of ASD.

scholarly journals Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

2020 ◽  
Author(s):  
Megha Amar ◽  
Akula Bala Pramod ◽  
Nam-Kyung Yu ◽  
Victor Munive Herrera ◽  
Lily R. Qiu ◽  
...  
Keyword(s):  
Brain Development ◽  
Brain Mri ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Small Gtpase ◽  
Mutant Mice ◽  
Network Activity ◽  
Proteomic Profiling ◽  
Filamentous Actin ◽  
Early Postnatal Development

SummaryE3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for Autism Spectrum Disorder (ASD) and Developmental Delay (DD). To investigate how Cul3 mutations impact brain development, we generated haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of the brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified neuronal cytoskeleton and Rho signaling as primary targets of Cul3 mutation during early brain development.

scholarly journals Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling

2019 ◽  
Vol 30 (5) ◽  
pp. 3240-3258 ◽  
Author(s):  
Jian-Wei Zhu ◽  
Ming-Ming Zou ◽  
Yi-Fei Li ◽  
Wen-Jin Chen ◽  
Ji-Chuan Liu ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Autism Spectrum ◽  
Mtor Signaling ◽  
Gabaergic Interneuron ◽  
Gabaergic Interneurons ◽  
Protein Signaling ◽  
Pathological Mechanism ◽  
Lateral Ganglionic Eminence ◽  
Model Mouse ◽  
Mtor Activity

Abstract Mammalian target of rapamycin (mTOR) signaling plays essential roles in brain development. Hyperactive mTOR is an essential pathological mechanism in autism spectrum disorder (ASD). Here, we show that tripartite motif protein 32 (TRIM32), as a maintainer of mTOR activity through promoting the proteasomal degradation of G protein signaling protein 10 (RGS10), regulates the proliferation of medial/lateral ganglionic eminence (M/LGE) progenitors. Deficiency of TRIM32 results in an impaired generation of GABAergic interneurons and autism-like behaviors in mice, concomitant with an elevated autophagy, which can be rescued by treatment embryonically with 3BDO, an mTOR activator. Transplantation of M/LGE progenitors or treatment postnatally with clonazepam, an agonist of the GABAA receptor, rescues the hyperexcitability and the autistic behaviors of TRIM32−/− mice, indicating a causal contribution of GABAergic disinhibition. Thus, the present study suggests a novel mechanism for ASD etiology in that TRIM32 deficiency-caused hypoactive mTOR, which is linked to an elevated autophagy, leads to autism-like behaviors via impairing generation of GABAergic interneurons. TRIM32−/− mouse is a novel autism model mouse.

scholarly journals CB1 antagonism increases excitatory synaptogenesis in a cortical spheroid model of fetal brain development

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexis Papariello ◽  
David Taylor ◽  
Ken Soderstrom ◽  
Karen Litwa
Keyword(s):  
Brain Development ◽  
Spontaneous Activity ◽  
Microelectrode Array ◽  
Cannabinoid Receptor ◽  
Fetal Brain ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Inhibitory Synapses ◽  
Fetal Brain Development

AbstractThe endocannabinoid system (ECS) plays a complex role in the development of neural circuitry during fetal brain development. The cannabinoid receptor type 1 (CB1) controls synaptic strength at both excitatory and inhibitory synapses and thus contributes to the balance of excitatory and inhibitory signaling. Imbalances in the ratio of excitatory to inhibitory synapses have been implicated in various neuropsychiatric disorders associated with dysregulated central nervous system development including autism spectrum disorder, epilepsy, and schizophrenia. The role of CB1 in human brain development has been difficult to study but advances in induced pluripotent stem cell technology have allowed us to model the fetal brain environment. Cortical spheroids resemble the cortex of the dorsal telencephalon during mid-fetal gestation and possess functional synapses, spontaneous activity, an astrocyte population, and pseudo-laminar organization. We first characterized the ECS using STORM microscopy and observed synaptic localization of components similar to that which is observed in the fetal brain. Next, using the CB1-selective antagonist SR141716A, we observed an increase in excitatory, and to a lesser extent, inhibitory synaptogenesis as measured by confocal image analysis. Further, CB1 antagonism increased the variability of spontaneous activity within developing neural networks, as measured by microelectrode array. Overall, we have established that cortical spheroids express ECS components and are thus a useful model for exploring endocannabinoid mediation of childhood neuropsychiatric disease.

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.

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 An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum

2021 ◽  
Vol 15 ◽  
Author(s):  
Esther Suk King Lai ◽  
Hisako Nakayama ◽  
Taisuke Miyazaki ◽  
Takanobu Nakazawa ◽  
Katsuhiko Tabuchi ◽  
...  
Keyword(s):  
Cell Adhesion Molecule ◽  
Synapse Formation ◽  
Single Point ◽  
Autism Spectrum ◽  
Mutant Mice ◽  
Single Point Mutation ◽  
Synapse Elimination ◽  
Wild Type ◽  
Post Mortem Brain ◽  
And Function

Neuroligin is a postsynaptic cell-adhesion molecule that is involved in synapse formation and maturation by interacting with presynaptic neurexin. Mutations in neuroligin genes, including the arginine to cystein substitution at the 451st amino acid residue (R451C) of neuroligin-3 (NLGN3), have been identified in patients with autism spectrum disorder (ASD). Functional magnetic resonance imaging and examination of post-mortem brain in ASD patients implicate alteration of cerebellar morphology and Purkinje cell (PC) loss. In the present study, we examined possible association between the R451C mutation in NLGN3 and synaptic development and function in the mouse cerebellum. In NLGN3-R451C mutant mice, the expression of NLGN3 protein in the cerebellum was reduced to about 10% of the level of wild-type mice. Elimination of redundant climbing fiber (CF) to PC synapses was impaired from postnatal day 10–15 (P10–15) in NLGN3-R451C mutant mice, but majority of PCs became mono-innervated as in wild-type mice after P16. In NLGN3-R451C mutant mice, selective strengthening of a single CF relative to the other CFs in each PC was impaired from P16, which persisted into juvenile stage. Furthermore, the inhibition to excitation (I/E) balance of synaptic inputs to PCs was elevated, and calcium transients in the soma induced by strong and weak CF inputs were reduced in NLGN3-R451C mutant mice. These results suggest that a single point mutation in NLGN3 significantly influences the synapse development and refinement in cerebellar circuitry, which might be related to the pathogenesis of ASD.

scholarly journals Autism as a disorder of neural information processing: Directions for research and targets for therapy

2019 ◽  
Author(s):  
Matthew Belmonte ◽  
John Rubenstein
Keyword(s):  
Brain Development ◽  
Autism Spectrum ◽  
Behavioural Syndrome ◽  
Neural Systems ◽  
Developmental Courses ◽  
Genetic Syndromes ◽  
Causal Factors ◽  
Neural Information ◽  
Neural Information Processing ◽  
Broad Variation

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.

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