Neuronal and glial cell number is altered in a cortical layer-specific manner in autism

Autism ◽  
2021 ◽  
pp. 136236132110144
Author(s):  
Carmen Falcone ◽  
Natalie-Ya Mevises ◽  
Tiffany Hong ◽  
Brett Dufour ◽  
Xiaohui Chen ◽  
...  

Autism spectrum disorder is a neurodevelopmental condition characterized by impaired social communication and repetitive behaviors. Changes in the number of specific cell types in the cerebral cortex could produce a dramatic alteration in the regulation of cortical circuits, and thus an alteration of behavior. We investigated whether there are layer-specific changes in the number of neurons, astrocytes, and oligodendrocytes in the prefrontal cortex in postmortem human brains from autism spectrum disorder subjects. We quantified the number of specific cell types in the prefrontal cortex (Brodmann areas 9, 46, and 47) of 10 cases with autism spectrum disorder and 10 age-matched control cases. We found that the number of neurons was increased and the number of astrocytes was decreased in layer II of all three prefrontal areas. Area BA47 was most widely affected presenting with an increased number of neurons and a decreased number of astrocytes in layer II and deeper layers of the cortex. Among other possibilities, the alterations in neuron and glial cell number we report here are consistent with a failure of radial glial cells to shift daughter cell production from neurons to astrocytes during prenatal cortical development in autism spectrum disorder. The data provided here are key anatomical findings that shed light on autism spectrum disorder pathogenesis. Lay abstract The cerebral cortex affected with autism spectrum disorder presents changes in the number of neurons and glia cells, possibly leading to a dysregulation of brain circuits and affecting behavior. However, little is known about cell number alteration in specific layers of the cortex in autism spectrum disorder. We found an increase in the number of neurons and a decrease in the number of astrocytes in specific layers of the prefrontal cortex in postmortem human brains from autism spectrum disorder cases. We hypothesize that this may be due to a failure in neural stem cells to shift differentiation from neurons to glial cells during prenatal brain development. These data provide key anatomical findings that contribute to the bases of autism spectrum disorder pathogenesis.

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Job O. de Jong ◽  
Ceyda Llapashtica ◽  
Matthieu Genestine ◽  
Kevin Strauss ◽  
Frank Provenzano ◽  
...  

AbstractWe utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.


2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jiujun Qiu ◽  
Xuejun Kong ◽  
Jihan Li ◽  
Jie Yang ◽  
Yiting Huang ◽  
...  

Recently, transcranial direct current stimulation (tDCS) has been applied to relieve symptoms in individuals with autism spectrum disorder (ASD). In this prospective, parallel, single-blinded, randomized study, we investigate the modulation effect of three-week tDCS treatment at the left dorsal lateral prefrontal cortex (DLPFC) in children with ASD. 47 children with ASD were enrolled, and 40 (20 in each group) completed the study. The primary outcomes are Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), and the Repetitive Behavior Scale-Revised (RBS-R). We found that children with ASD can tolerate three-week tDCS treatment with no serious adverse events detected. A within-group comparison showed that real tDCS, but not sham tDCS, can significantly reduce the scores of CARS, Children’s Sleep Habits Questionnaire (CSHQ), and general impressions in CARS (15th item). Real tDCS produced significant score reduction in the CSHQ and in CARS general impressions when compared to the effects of sham tDCS. The pilot study suggests that three-week left DLPFC tDCS is well-tolerated and may hold potential in relieving some symptoms in children with ASD.


2017 ◽  
Vol 81 (10) ◽  
pp. S53
Author(s):  
Cynthia Kiefer ◽  
Maria Kryza-Lacombe ◽  
Katrina Cole ◽  
Catherine Lord ◽  
Christopher Monk ◽  
...  

Heliyon ◽  
2017 ◽  
Vol 3 (11) ◽  
pp. e00468 ◽  
Author(s):  
Manabu Makinodan ◽  
Kazuki Okumura ◽  
Daisuke Ikawa ◽  
Yasunori Yamashita ◽  
Kazuhiko Yamamuro ◽  
...  

2020 ◽  
Author(s):  
Sarah Jacot-Descombes ◽  
Neha U Keshav ◽  
Dara L. Dickstein ◽  
Bridget Wicinski ◽  
William G. M. Janssen ◽  
...  

Abstract Background Deletion or mutations of SHANK3 lead to Phelan-McDermid syndrome and monogenic forms of autism spectrum disorder. SHANK3 encodes its eponymous scaffolding protein at excitatory glutamatergic synapses. Altered dendritic and spine morphology in the hippocampus, cerebellum and striatum have been associated with behavioral impairments in various Shank3-deficient animal models. Given the attentional deficit reported in these animals, our study explored whether deficiency of Shank3 in a rat model alters synaptic ultrastructure in the medial prefrontal cortex. Methods We used electron microscopy to determine the density of asymmetric synapses in layer III excitatory neurons of the medial prefrontal cortex in 5 week-old Shank3-homozygous knockout ( Shank3 -KO), heterozygous ( Shank3 -Het), and wild-type (WT) rats. We also measured postsynaptic density length, postsynaptic density area, and head diameter of dendritic spines at these synapses. Results All three groups had comparable synapse density and postsynaptic density length. Spine head diameter of Shank3 -Het rats, but not Shank3 -KO, was larger than WT rats. Shank3 -Het rats had wider head diameter in non-perforated synapses compared to WT and Shank3 -KO rats. The total postsynaptic density area was significantly larger in Shank3 -Het rats compared to Shank3 -KO and WT rats. These findings represent preliminary evidence for synaptic ultrastructural alterations in the medial prefrontal cortex of rats that lack one copy of Shank3 and mimic the heterozygous loss of SHANK3 in Phelan-McDermid syndrome. Limitations The Shank3 deletion in the rat model we used does not affect all isoforms of the protein and as such, would only model the effect of the mutations resulting in loss of the N-terminus of the protein. Given the higher prevalence of ASD in males, this study focused only on synaptic ultrastructure in male Shank3 -deficient rats. Conclusions We observed increased head diameter and postsynaptic density area in rats heterozygous for Shank3 deficiency. Further investigations of the mechanisms leading to altered synaptic ultrastructure in this animal model will enable us to understand better the role that Shank3 protein plays in autism spectrum disorder and Phelan-McDermid syndrome.


2017 ◽  
Vol 7 (5) ◽  
pp. e1137-e1137 ◽  
Author(s):  
L A Ajram ◽  
J Horder ◽  
M A Mendez ◽  
A Galanopoulos ◽  
L P Brennan ◽  
...  

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