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Published on: May 12, 2015
Excitatory and Inhibitory Synaptic Imbalance Caused by Brain-Derived Neurotrophic Factor Deficits During Development
Chuchu Qi1, Andi Chen1, Honghui Mao1
1Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Insights
Valproic acid (VPA) during pregnancy disrupts brain development, causing autism spectrum disorder (ASD) by impairing synaptic function and brain-derived neurotrophic factor (BDNF) levels. Supplementing BDNF in a mouse model reversed these autism-like behaviors.
Area of Science:
- Neuroscience
- Developmental Biology
- Autism Spectrum Disorder Research
Background:
- Environmental factors, including prenatal medication exposure, are significant contributors to autism spectrum disorder (ASD).
- Valproic acid (VPA) exposure during pregnancy is a known risk factor for ASD, potentially by inducing synaptic dysfunction.
- The precise mechanisms by which VPA alters the excitatory/inhibitory (E/I) balance in ASD development remain under investigation.
Purpose of the Study:
- To investigate the developmental changes in the E/I balance in a VPA-induced mouse model of ASD.
- To determine the role of brain-derived neurotrophic factor (BDNF) in VPA-induced synaptic dysfunction and autism-like behaviors.
- To assess the therapeutic potential of exogenous BDNF in ameliorating ASD-related deficits.
Main Methods:
- Utilized a VPA mouse model to study developmental E/I balance.
- Assessed pre- and postsynaptic markers of excitatory and inhibitory function.
- Measured brain-derived neurotrophic factor (BDNF) expression levels.
- Administered exogenous BDNF during a critical developmental window.
- Evaluated synaptic function and autism-like behaviors, including social deficits.
Main Results:
- VPA exposure led to a significant decrease in markers of both excitatory and inhibitory synaptic function during development.
- Reduced expression of BDNF was observed in VPA-exposed mice, correlating with impaired synaptic plasticity.
- Treatment with exogenous BDNF successfully restored synaptic function and rescued social deficits in the VPA mouse model.
- These findings suggest a critical role for BDNF in mediating the effects of VPA on E/I balance and social behavior.
Conclusions:
- Developmental E/I imbalance, driven by BDNF deficits, contributes to social dysfunction in the VPA mouse model of autism.
- Restoring BDNF levels during critical developmental periods can rescue synaptic abnormalities and autism-like behaviors.
- This study highlights BDNF as a potential therapeutic target for ASD associated with prenatal VPA exposure.
Abstract:
Environmental factors, such as medication during pregnancy, are one of the major causes of autism spectrum disorder (ASD). Valproic acid (VPA) intake during pregnancy has been reported to dramatically elevate autism risk in offspring. Recently, researchers have proposed that VPA exposure could induce excitatory or inhibitory synaptic dysfunction. However, it remains to be determined whether and how alterations in the excitatory/inhibitory (E/I) balance contribute to VPA-induced ASD in a mouse model. In the present study, we explored changes in the E/I balance during different developmental periods in a VPA mouse model. We found that typical markers of pre- and postsynaptic excitatory and inhibitory function involved in E/I balance markedly decreased during development, reflecting difficulties in the development of synaptic plasticity in VPA-exposed mice. The expression of brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the formation and maturation of glutamatergic and GABAergic synapses during postnatal development, was severely reduced in the VPA-exposed group. Treatment with exogenous BDNF during the critical E/I imbalance period rescued synaptic functions and autism-like behaviors, such as social defects. With these results, we experimentally showed that social dysfunction in the VPA mouse model of autism might be caused by E/I imbalance stemming from BDNF deficits during the developmental stage.
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