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Click on the blue letters to follow us TRIO is a member of the Dbl homologous guanine nucleotide exchange factor (DH-GEF) family.
It participates in Rho-GTPase signaling and is highly expressed on excitatory and inhibitory neurons during development.
Functional mutations in the GEF1 domain of TRIO are closely related to autism.
The core hypothesis of autism is excitatory/inhibitory imbalance: too many excitatory signals or too few inhibitory signals.
Clinical studies have shown that in patients with autism, there is a decrease in the number of mesenteric neurons in the cortex and hippocampus, and the expression of GABA receptors is decreased.
Although autism risk genes related to the GABAergic pathway have been identified, most studies have focused on GABAergic inhibitory neurons in the mature stage.
On May 7, 2021, the research team of Li Jun/Zhang Dai from Peking University Sixth Hospital published an article in Nature, revealing the mechanism of autism-like behavior disorder caused by TRIO, a high-risk factor for autism, by regulating the migration of mesenteric neurons during embryonic development.
.
After all Trio is knocked out, the number of embryonic inhibitory neurons that migrate from the ganglion uplift to the cortex is reduced, and the proportion of migration to the ventricular zone (VZ) and subventricular zone (SVZ) increases.
Behavioral experiments found that Trio heterozygous mutant mice showed severe social disorders, repetitive stereotyped behaviors and other autism-like behavior disorders in adulthood.
Trio knockout mice have abnormal migration of inhibitory neurons.
They further specifically knocked out Trio (Trio-Dlx5/6-CIE mice) on inhibitory neural precursor cells at the uplift of embryonic ganglion, and the number of inhibitory neurons was in The distribution of the entire brain area changed: the density of inhibitory neurons in the hippocampal DG area and mPFC brain area decreased, but there was no change in the somatosensory cortex, striatum, and amygdala.In addition, the distribution of inhibitory neuron subtypes such as calcium binding protein positive, somatostatin positive, and vasoactive intestinal peptide positive in the hippocampus and mPFC also changed.
This indicates that knocking out Trio on inhibitory neural precursor cells during the embryonic period caused abnormal migration of inhibitory neurons, specifically changing the distribution of inhibitory neuron subtypes and numbers in mPFC and hippocampal brain regions.
In addition, Trio-Dlx5/6-CIE mice had more branches of inhibitory neurons, but the total length of the branches was significantly reduced.
At the same time, the number of excitatory neurons and inhibitory synapses around the mPFC brain area was significantly reduced, but the number of excitatory synapses did not change.
Electrophysiological experiments also found that the tiny inhibitory postsynaptic currents of Trio-Dlx5/6-CIE mice were weakened, which indicated that there was an excitatory/inhibitory imbalance.
Like Trio heterozygous mutations, Trio-Dlx5/6-CIE mice also exhibit obvious autistic behavior disorders.
Most autism-related exon sequencing studies have shown that TRIO's GEF1 domain mutation is closely related to autism.
In order to further verify the association between TRIO’s GEF1 domain mutation and abnormal intermediate inhibitory neurons, the researchers constructed Trio K1431M mice, which completely replicated the characteristics of all-knockout Trio: abnormal migration of inhibitory neurons, tiny Inhibitory postsynaptic currents are weakened, excitatory/inhibitory imbalances, and autistic behavior disorders appear.
Intraperitoneal injection of low-dose GABA receptor agonists can alleviate the aforementioned autistic behavior disorders.
In summary, this article describes the excitatory/inhibitory imbalance mediated by intermediate inhibitory neuron migration disorders to regulate autism-like behavioral disorders from the perspective of embryonic development, and provides new strategies for the treatment of autism.
[References] 1.
https://doi.
org/10.
1038/s41380-021-01109-x The pictures in the article are all from the references
It participates in Rho-GTPase signaling and is highly expressed on excitatory and inhibitory neurons during development.
Functional mutations in the GEF1 domain of TRIO are closely related to autism.
The core hypothesis of autism is excitatory/inhibitory imbalance: too many excitatory signals or too few inhibitory signals.
Clinical studies have shown that in patients with autism, there is a decrease in the number of mesenteric neurons in the cortex and hippocampus, and the expression of GABA receptors is decreased.
Although autism risk genes related to the GABAergic pathway have been identified, most studies have focused on GABAergic inhibitory neurons in the mature stage.
On May 7, 2021, the research team of Li Jun/Zhang Dai from Peking University Sixth Hospital published an article in Nature, revealing the mechanism of autism-like behavior disorder caused by TRIO, a high-risk factor for autism, by regulating the migration of mesenteric neurons during embryonic development.
.
After all Trio is knocked out, the number of embryonic inhibitory neurons that migrate from the ganglion uplift to the cortex is reduced, and the proportion of migration to the ventricular zone (VZ) and subventricular zone (SVZ) increases.
Behavioral experiments found that Trio heterozygous mutant mice showed severe social disorders, repetitive stereotyped behaviors and other autism-like behavior disorders in adulthood.
Trio knockout mice have abnormal migration of inhibitory neurons.
They further specifically knocked out Trio (Trio-Dlx5/6-CIE mice) on inhibitory neural precursor cells at the uplift of embryonic ganglion, and the number of inhibitory neurons was in The distribution of the entire brain area changed: the density of inhibitory neurons in the hippocampal DG area and mPFC brain area decreased, but there was no change in the somatosensory cortex, striatum, and amygdala.In addition, the distribution of inhibitory neuron subtypes such as calcium binding protein positive, somatostatin positive, and vasoactive intestinal peptide positive in the hippocampus and mPFC also changed.
This indicates that knocking out Trio on inhibitory neural precursor cells during the embryonic period caused abnormal migration of inhibitory neurons, specifically changing the distribution of inhibitory neuron subtypes and numbers in mPFC and hippocampal brain regions.
In addition, Trio-Dlx5/6-CIE mice had more branches of inhibitory neurons, but the total length of the branches was significantly reduced.
At the same time, the number of excitatory neurons and inhibitory synapses around the mPFC brain area was significantly reduced, but the number of excitatory synapses did not change.
Electrophysiological experiments also found that the tiny inhibitory postsynaptic currents of Trio-Dlx5/6-CIE mice were weakened, which indicated that there was an excitatory/inhibitory imbalance.
Like Trio heterozygous mutations, Trio-Dlx5/6-CIE mice also exhibit obvious autistic behavior disorders.
Most autism-related exon sequencing studies have shown that TRIO's GEF1 domain mutation is closely related to autism.
In order to further verify the association between TRIO’s GEF1 domain mutation and abnormal intermediate inhibitory neurons, the researchers constructed Trio K1431M mice, which completely replicated the characteristics of all-knockout Trio: abnormal migration of inhibitory neurons, tiny Inhibitory postsynaptic currents are weakened, excitatory/inhibitory imbalances, and autistic behavior disorders appear.
Intraperitoneal injection of low-dose GABA receptor agonists can alleviate the aforementioned autistic behavior disorders.
In summary, this article describes the excitatory/inhibitory imbalance mediated by intermediate inhibitory neuron migration disorders to regulate autism-like behavioral disorders from the perspective of embryonic development, and provides new strategies for the treatment of autism.
[References] 1.
https://doi.
org/10.
1038/s41380-021-01109-x The pictures in the article are all from the references
