Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function DOI Creative Commons
Daji Guo, Yinghui Peng, Laijian Wang

и другие.

Molecular Psychiatry, Год журнала: 2019, Номер 26(5), С. 1505 - 1519

Опубликована: Авг. 6, 2019

Genetic studies of autism spectrum disorder (ASD) have revealed multigene variations that converge on synaptic dysfunction. DOCK4, a gene at 7q31.1 encodes the Rac1 guanine nucleotide exchange factor Dock4, has been identified as risk for ASD and other neuropsychiatric disorders. However, whether how Dock4 disruption leads to features through mechanism remain unexplored. We generated characterized line knockout (KO) mice, which intriguingly displayed series ASD-like behaviors, including impaired social novelty preference, abnormal isolation-induced pup vocalizations, elevated anxiety, perturbed object spatial learning. Mice with conditional deletion in hippocampal CA1 recapitulated preference deficit KO mice. Examination pyramidal neurons excitatory transmission was drastically attenuated accompanied by decreased spine density content AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)- NMDA (N-methyl-D-aspartate)-type glutamate receptors. Moreover, deficiency markedly reduced activity hippocampus, resulted downregulation global protein synthesis diminished expression receptor subunits. Notably, replenishment mice restored corrected deficits these pharmacological activation receptors also Together, our findings uncover previously unrecognized Dock4-Rac1-dependent involved regulating behavior.

Язык: Английский

Dendritic structural plasticity and neuropsychiatric disease DOI
Marc P. Forrest, Euan Parnell, Peter Penzes

и другие.

Nature reviews. Neuroscience, Год журнала: 2018, Номер 19(4), С. 215 - 234

Опубликована: Март 16, 2018

Язык: Английский

Процитировано

424
The ASD Living Biology: from cell proliferation to clinical phenotype DOI Creative Commons
Eric Courchesne, Tiziano Pramparo, Vahid Gazestani

и другие.

Molecular Psychiatry, Год журнала: 2018, Номер 24(1), С. 88 - 107

Опубликована: Июнь 19, 2018

Abstract Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and lay public because its uncertain origins striking unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, cell model evidence that shows ASD begins in womb. This leads to a new theory is multistage, progressive brain development, spanning nearly all prenatal life. can begin as early 1st 2nd trimester with disruption proliferation differentiation. It continues neural migration, laminar disorganization, altered neuron maturation neurite outgrowth, synaptogenesis reduced network functioning. Among most commonly reported high-confidence ( hcASD ) genes, 94% express during life affect these fetal processes neocortex, amygdala, hippocampus, striatum cerebellum. A majority genes are pleiotropic, proliferation/differentiation and/or synapse development. Proliferation subsequent stages also be disrupted by maternal immune activation trimester. Commonly implicated pathways, PI3K/AKT RAS/ERK, pleiotropic multiple from through functional In different individuals, variation how when pathways dysregulated, will lead different, even opposing effects, producing well later Thus, pathogenesis not set at one point time does reside process, but rather cascade pathogenic vast toddlers. Despite this knowledge biology womb, current research methods have provided individualized information: What early-age molecular cellular differences underlie each individual child? Without such knowledge, rapid advances biological-based diagnostic, prognostic, precision medicine treatments cannot occur. Missing, therefore, what call Living Biology. conceptual paradigm shift towards focus on abnormal underlying within living individual. The concept emphasizes specific need for foundational child’s development beginnings stages. Biology seeks linking genetic vitro molecular, measurements vivo post-natal presentation progression child. We first study, which confirms multistage nature provides fetal-stage explanation overgrowth. Within-child novel coin here advocates integration information generate group-level explanations, clinically useful prognoses, approaches truly beneficial infant toddler ASD.

Язык: Английский

Процитировано

284
A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders DOI Creative Commons
Claudia Bagni, R. Suzanne Zukin

Neuron, Год журнала: 2019, Номер 101(6), С. 1070 - 1088

Опубликована: Март 1, 2019

Язык: Английский

Процитировано

282
Synaptopathology Involved in Autism Spectrum Disorder DOI Creative Commons

Shiqi Guang,

Nan Pang,

Xiaolu Deng

и другие.

Frontiers in Cellular Neuroscience, Год журнала: 2018, Номер 12

Опубликована: Дек. 21, 2018

Autism spectrum disorder (ASD) is a group of multifactorial neurodevelopmental disorders characterized by impaired social communication, interaction and repetitive behaviors. ASD affected 1 in 59 children, about 4 times more common among boys than girls. There strong genetic component to susceptibility, conjunction with developmental early environmental factors, together contribute the pathogenesis ASD. Multiple studies have unveiled that mutations genes like NRXN, NLGN, SHANK, TSC1/2, FMR1 MECP2 converge on cellular pathways intersect at synapses. These gene products encompass cell adhesion molecules, scaffolding proteins, regulators transcription protein levels, affecting synapses various aspects including synapse formation elimination, synaptic transmission plasticity, which suggests ASD, least part, be attributed dysfunction. In this review article, we focus major signaling implicated abnormalities underlying discuss molecular, functional animal models.

Язык: Английский

Процитировано

250
Anterior cingulate cortex dysfunction underlies social deficits in Shank3 mutant mice DOI
Baolin Guo, Jing Chen, Qian Chen

и другие.

Nature Neuroscience, Год журнала: 2019, Номер 22(8), С. 1223 - 1234

Опубликована: Июль 22, 2019

Язык: Английский

Процитировано

230
Inhibitory control of the excitatory/inhibitory balance in psychiatric disorders DOI Creative Commons
Martijn Selten, Hans van Bokhoven, Nael Nadif Kasri

и другие.

F1000Research, Год журнала: 2018, Номер 7, С. 23 - 23

Опубликована: Янв. 8, 2018

Neuronal networks consist of different types neurons that all play their own role in order to maintain proper network function. The two main segregate excitatory and inhibitory neurons, which together regulate the flow information through network. It has been proposed changes relative strength these opposing forces underlie symptoms observed psychiatric disorders, including autism schizophrenia. Here, we review alterations function system as a cause disorders. First, explore both patient post-mortem evidence deficiency. We then discuss interneuron subtypes focus on central specific class parvalbumin-positive interneurons. Finally, genes known be affected disorders effects mutations have cortex hippocampus. conclude are consistently identified animal models and, more specifically, affecting interneurons seem disorders.

Язык: Английский

Процитировано

199
The Autism-Associated Gene Scn2a Contributes to Dendritic Excitability and Synaptic Function in the Prefrontal Cortex DOI Creative Commons

Perry W.E. Spratt,

Roy Ben‐Shalom,

Caroline M. Keeshen

и другие.

Neuron, Год журнала: 2019, Номер 103(4), С. 673 - 685.e5

Опубликована: Июнь 20, 2019

Язык: Английский

Процитировано

197
Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications DOI Creative Commons

Chen-Chen Jiang,

Lishan Lin,

Sen Long

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Июль 11, 2022

Autism spectrum disorder (ASD) is a prevalent and complex neurodevelopmental which has strong genetic basis. Despite the rapidly rising incidence of autism, little known about its aetiology, risk factors, disease progression. There are currently neither validated biomarkers for diagnostic screening nor specific medication autism. Over last two decades, there have been remarkable advances in genetics, with hundreds genes identified as being associated high The convergence neuroscience methods becoming more widely recognized significance elucidating pathological mechanisms Efforts devoted to exploring behavioural functions, key potential treatments Here, we highlight this review, emerging evidence shows that signal transduction molecular events involved processes such transcription, translation, synaptic transmission, epigenetics immunoinflammatory responses. This involvement important implications discovery precise targets Moreover, review recent insights into clinical autism from molecular, cellular, neural circuit, neurobehavioural aspects. Finally, challenges future perspectives discussed regard novel strategies predicated on biological features

Язык: Английский

Процитировано

141
Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment DOI
Cleber A. Trujillo, Edward S. Rice, Nathan K. Schaefer

и другие.

Science, Год журнала: 2021, Номер 371(6530)

Опубликована: Фев. 11, 2021

Brain organoids with Neanderthal genes The genomes of Neanderthals and modern humans are overall very similar. To understand the impact genetic variants that specific to humans, Trujillo et al. performed a genome-wide analysis identify 61 coding in protein-coding genes. Identifying gene encoding RNA-binding protein NOVA1 as top candidate for functional analyses, they introduced archaic variant into human pluripotent stem cells generated brain organoids. These showed alterations expression splicing well morphology synaptogenesis, suggesting this method could be used explore other changes underlie phenotypic traits separating our species from extinct relatives. Science , issue p. eaax2537

Язык: Английский

Процитировано

115
Linking mPFC circuit maturation to the developmental regulation of emotional memory and cognitive flexibility DOI Creative Commons

Cassandra B. Klune,

Benita Jin, Laura A. DeNardo

и другие.

eLife, Год журнала: 2021, Номер 10

Опубликована: Май 5, 2021

The medial prefrontal cortex (mPFC) and its abundant connections with other brain regions play key roles in memory, cognition, decision making, social behaviors, mood. Dysfunction mPFC is implicated psychiatric disorders which these behaviors go awry. prolonged maturation of likely enables complex to emerge, but also increases their vulnerability disruption. Many foundational studies have characterized either synaptic or behavioral development without establishing between them. Here, we review this rich body literature, aligning major events the behaviors. We focus on emotional memory cognitive flexibility, highlight new work linking circuit disruption alterations disease models. advance hypotheses about causal propose research strategies establish an integrated understanding neural architecture repertoires.

Язык: Английский

Процитировано

113