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Editor | Enzyme Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder.
Its core symptoms are impaired social interaction and communication, and repetitive stereotyped behaviors; WHO data shows the incidence of ASD in children worldwide It is 1/160, but its pathogenesis is still unclear, and there is no effective treatment drug
.
Previous research work has mainly focused on the role of neurons in the pathogenesis of autism, but some recent evidence suggests that abnormal astrocytes may also play an important role in the pathogenesis of autism
.
For example, autopsy results and animal models of patients with autism have found that the expression levels of astrocyte markers such as GFAP, S100β, AQP-4, connexin 43, and EAAT1 have changed
.
In particular, astrocytes derived from induced pluripotent stem cells from patients with autism can impair the development and function of cultured neurons; while astrocytes derived from normal human induced pluripotent stem cells can save the culture Morphological and functional defects of neurons in ASD patients
.
These findings suggest that astrocytes may be involved in the pathological process of autism
.
However, the causal relationship between astrocyte dysfunction and autism is still unclear
.
Recently, the team of Professor Tianming Gao from Southern Medical University published a research paper entitled Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice in Nature Communications, which discussed the role of astrocytes in the pathogenesis of autism.
And conducted in-depth research on its molecular mechanism
.
Astrocytes are the most numerous cell type in the central nervous system, and more and more evidence shows that they play a pivotal role in regulating brain function
.
Astrocyte activation is mainly manifested as an increase in intracellular calcium signal mediated by the inositol triphosphate type 2 receptor (IP3R2), and mutations in the IP3R2 gene are associated with autism, but it is not clear what is caused by IP3R2 deficiency.
Whether glial cell disorder is involved in the pathological process of autism
.
The authors used gene knockout technology to prepare IP3R2 whole body knockout mice (KO) and astrocyte conditional knockout mice (cKO), and performed behavioral screening, and found KO and cKO mice All showed abnormal calcium signal in astrocytes and the core symptoms of autism, namely impaired social function and repetitive stereotyped behaviors
.
At the same time, after using the AAV virus to specifically knock down the IP3R2 receptor of astrocytes in the prefrontal cortex, the mice also showed similar cellular and behavioral abnormalities
.
The above evidence indicates that abnormal function of astrocytes is involved in the occurrence and development of autistic behaviors
.
In the exploration of the mechanism, the authors used microdialysis, cell culture, and new ATP probes to determine that the reduction of ATP released by astrocytes may be the cause of autistic behavior
.
Exogenous administration of ATP can reverse the autism-like behavior of animals, indicating that abnormal ATP release from astrocytes is an important link in the occurrence of autism
.
The authors performed electrophysiological examinations on KO and cKO mice and found that the GABAergic synaptic transmission in the medial prefrontal cortex of the two gene knockout mice was impaired, while the glutamatergic synaptic transmission was not affected.
The impaired GABAergic Synaptic transmission can be reversed by ATP, and GABA receptor agonists can also improve autistic behavior in animals
.
Further through virological means to interfere with the ATP receptor P2X2, it was found that knocking down the P2X2 receptor not only blocked the improvement effect of ATP on GABAergic synaptic transmission, but also blocked the therapeutic effect of ATP on autistic behavior
.
The above results indicate that ATP regulates GABAergic synaptic transmission and autism-like behavior through the P2X2 receptor
.
In summary, this study reported for the first time that astrocytes are involved in the occurrence of autism.
The mechanism is that the reduction of ATP released by astrocytes weakens GABAergic synaptic transmission through P2X2 receptors, which leads to the occurrence of autism.
.
Depression and autism are highly comorbidities.
Combined with the team’s previous report that astrocyte-derived ATP mediates the occurrence of depression (Cao et al.
, Nat Med 2013), it suggests that the pathological mechanism may be These two diseases are shared, and drugs developed for this target are expected to have the effect of treating both diseases
.
Original link: https:// Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is allowed, the author has all legal rights, and offenders must be investigated
.
Its core symptoms are impaired social interaction and communication, and repetitive stereotyped behaviors; WHO data shows the incidence of ASD in children worldwide It is 1/160, but its pathogenesis is still unclear, and there is no effective treatment drug
.
Previous research work has mainly focused on the role of neurons in the pathogenesis of autism, but some recent evidence suggests that abnormal astrocytes may also play an important role in the pathogenesis of autism
.
For example, autopsy results and animal models of patients with autism have found that the expression levels of astrocyte markers such as GFAP, S100β, AQP-4, connexin 43, and EAAT1 have changed
.
In particular, astrocytes derived from induced pluripotent stem cells from patients with autism can impair the development and function of cultured neurons; while astrocytes derived from normal human induced pluripotent stem cells can save the culture Morphological and functional defects of neurons in ASD patients
.
These findings suggest that astrocytes may be involved in the pathological process of autism
.
However, the causal relationship between astrocyte dysfunction and autism is still unclear
.
Recently, the team of Professor Tianming Gao from Southern Medical University published a research paper entitled Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice in Nature Communications, which discussed the role of astrocytes in the pathogenesis of autism.
And conducted in-depth research on its molecular mechanism
.
Astrocytes are the most numerous cell type in the central nervous system, and more and more evidence shows that they play a pivotal role in regulating brain function
.
Astrocyte activation is mainly manifested as an increase in intracellular calcium signal mediated by the inositol triphosphate type 2 receptor (IP3R2), and mutations in the IP3R2 gene are associated with autism, but it is not clear what is caused by IP3R2 deficiency.
Whether glial cell disorder is involved in the pathological process of autism
.
The authors used gene knockout technology to prepare IP3R2 whole body knockout mice (KO) and astrocyte conditional knockout mice (cKO), and performed behavioral screening, and found KO and cKO mice All showed abnormal calcium signal in astrocytes and the core symptoms of autism, namely impaired social function and repetitive stereotyped behaviors
.
At the same time, after using the AAV virus to specifically knock down the IP3R2 receptor of astrocytes in the prefrontal cortex, the mice also showed similar cellular and behavioral abnormalities
.
The above evidence indicates that abnormal function of astrocytes is involved in the occurrence and development of autistic behaviors
.
In the exploration of the mechanism, the authors used microdialysis, cell culture, and new ATP probes to determine that the reduction of ATP released by astrocytes may be the cause of autistic behavior
.
Exogenous administration of ATP can reverse the autism-like behavior of animals, indicating that abnormal ATP release from astrocytes is an important link in the occurrence of autism
.
The authors performed electrophysiological examinations on KO and cKO mice and found that the GABAergic synaptic transmission in the medial prefrontal cortex of the two gene knockout mice was impaired, while the glutamatergic synaptic transmission was not affected.
The impaired GABAergic Synaptic transmission can be reversed by ATP, and GABA receptor agonists can also improve autistic behavior in animals
.
Further through virological means to interfere with the ATP receptor P2X2, it was found that knocking down the P2X2 receptor not only blocked the improvement effect of ATP on GABAergic synaptic transmission, but also blocked the therapeutic effect of ATP on autistic behavior
.
The above results indicate that ATP regulates GABAergic synaptic transmission and autism-like behavior through the P2X2 receptor
.
In summary, this study reported for the first time that astrocytes are involved in the occurrence of autism.
The mechanism is that the reduction of ATP released by astrocytes weakens GABAergic synaptic transmission through P2X2 receptors, which leads to the occurrence of autism.
.
Depression and autism are highly comorbidities.
Combined with the team’s previous report that astrocyte-derived ATP mediates the occurrence of depression (Cao et al.
, Nat Med 2013), it suggests that the pathological mechanism may be These two diseases are shared, and drugs developed for this target are expected to have the effect of treating both diseases
.
Original link: https:// Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is allowed, the author has all legal rights, and offenders must be investigated
.
