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Updated: Sep 29, 2025
Utilizing In Vivo Postnatal Electroporation to Study Cerebellar Granule Neuron Morphology and Synapse Development
Published on: June 9, 2021
Progranulin improves neural development via the PI3K/Akt/GSK-3β pathway in the cerebellum of a VPA-induced rat model
Lili Wang1, Jianhui Chen1, Yuling Hu2
1Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016, China.
Insights
Progranulin (PGRN) levels decrease in autism spectrum disorder (ASD) models. Supplementing PGRN in rats improved social behaviors and reduced repetitive actions, suggesting a new therapeutic approach for ASD.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social deficits and repetitive behaviors, with increasing prevalence.
- Progranulin (PGRN), a neurotrophic factor, supports neuronal survival and differentiation, but its role in ASD animal models is understudied.
Purpose of the Study:
- To investigate the therapeutic effects of Progranulin (PGRN) on autistic phenotypes in a valproic acid (VPA)-induced rat model of ASD.
- To elucidate the underlying molecular mechanisms of PGRN's action in the cerebellum of this ASD rat model.
Main Methods:
- Valproic acid (VPA) was used to induce an ASD-like phenotype in rats.
- Cerebellar PGRN levels were measured at postnatal days 14 and 35.
- Recombinant human PGRN (r-PGRN) was administered intracerebellarly to VPA-exposed rats.
- Behavioral tests assessed social preference, repetitive behaviors, and motor coordination.
- Neuronal apoptosis and synapse formation were evaluated.
- The PI3K/Akt/GSK-3β pathway and prosaposin (PSAP) involvement were investigated.
Main Results:
- PGRN levels were significantly downregulated in the cerebellum of VPA-exposed rats.
- VPA-exposed rats exhibited social deficits, increased repetitive behaviors, and motor impairments.
- r-PGRN treatment alleviated some behavioral defects, reduced cerebellar neuronal apoptosis, and restored synapse formation.
- PGRN was confirmed to protect neurodevelopment via the PI3K/Akt/GSK-3β pathway.
- Prosaposin (PSAP) was found to enhance PGRN internalization and neurotrophic activity.
Conclusions:
- This study provides the first experimental evidence for the therapeutic potential of PGRN in a rat model of ASD.
- PGRN supplementation demonstrates promise in ameliorating core autistic behaviors and underlying neuropathology.
- The findings highlight PGRN and its interaction with PSAP as a novel therapeutic strategy for autism spectrum disorder.
Abstract:
Autism spectrum disorder (ASD) is a neurodevelopmental disease featuring social interaction deficits and repetitive/stereotyped behaviours; the prevalence of this disorder has continuously increased. Progranulin (PGRN) is a neurotrophic factor that promotes neuronal survival and differentiation. However, there have not been sufficient studies investigating its effect in animal models of autism. This study investigated the effects of PGRN on autistic phenotypes in rats treated with valproic acid (VPA) and assessed the underlying molecular mechanisms. PGRN was significantly downregulated in the cerebellum at postnatal day 14 (PND14) and PND35 in VPA-exposed rats, which simultaneously showed defective social preference, increased repetitive behaviours, and uncoordinated movements. When human recombinant PGRN (r-PGRN) was injected into the cerebellum of newborn ASD model rats (PND10 and PND17), some of the behavioural defects were alleviated. r-PGRN supplementation also reduced cerebellar neuronal apoptosis and rescued synapse formation in ASD rats. Mechanistically, we confirmed that PGRN protects neurodevelopment via the PI3K/Akt/GSK-3β pathway in the cerebellum of a rat ASD model. Moreover, we found that prosaposin (PSAP) promoted the internalisation and neurotrophic activity of PGRN. These results experimentally demonstrate the therapeutic effects of PGRN on a rat model of ASD for the first time and provide a novel therapeutic strategy for autism.
