Valproic Acid Induces Autism-Like Synaptic and Behavioral Deficits by Disrupting Histone Acetylation of Prefrontal Cortex ALDH1A1 in Rats

Abstract

ObjectivesThis study aimed to investigate the impact of valproic acid (VPA) on the histone acetylation of acetaldehyde dehydrogenase 1A1 (ALDH1A1) and the mechanism underlying VPA-induced autism-like behavior.MethodsFemale Sprague-Dawley rats were intraperitoneally injected with VPA during gestation to establish an autism model in their offspring. Some offspring prenatally exposed to VPA were randomly treated with MS-275, one histone deacetylase (HDAC) inhibitor, or retinoic acid (RA) after birth. Behavioral tests were conducted on the offspring 6 weeks after birth. Electrophysiological experiments were performed to investigate long-term potentiation (LTP) in the prefrontal cortex (PFC). The expression levels of AMPA receptors (GluA1 and 2), NMDA receptors (GluN1 and 2), synapsin 1 (SYN1), HDAC, acetylated histone 3 (AcH3), RA receptor alpha (RARα), and ALDH1A1 in the PFC were measured by Western blotting and quantitative polymerase chain reaction. ALDH enzyme activity in PFC tissue was detected using a Micro ALDH Assay Kit. The RA level in the PFC was measured using ultrahigh-performance liquid chromatography/tandem mass spectrometry. A chromatin immunoprecipitation (ChIP) experiment explored the interaction between the ALDH1A1 gene and AcH3.ResultsOffspring prenatally exposed to VPA showed autism-like behavior, upregulated the levels of LTP and GluN2A, GluA1, and SYN1 proteins relevant to synaptic plasticity in the PFC. The expression levels of HDAC3 mRNA and protein were increased. On the other hand, there was a significant reduction in the levels of AcH3, RARα, RA, ALDH1A1 mRNA and protein, the level of ALDH activity and AcH3 enrichment in the ALDH1A1 promoter region in VPA-induced offspring. Administration of MS-275 in VPA offspring significantly elevated the levels of AcH3, ALDH1A1 mRNA and protein, ALDH activity, RA, the level of RARα protein and the binding of AcH3 to the ALDH1A1 promoter. In addition, the GluA1 protein level and LTP were reduced, and most behavioral deficits were reversed. After RA supplementation in the VPA-treated offspring, the RA and RARα protein levels were significantly upregulated, GluA1 protein and LTP were downregulated, and most autism-like behavioral deficits were effectively reversed.ConclusionThese findings suggest that VPA impairs histoneacetylation of ALDH1A1 and downregulates the RA-RARα pathway. Such epigenetic modification of ALDH1A1 by VPA leads to autism-like synaptic and behavioral deficits.

iTRAQ-Based Proteomics Analysis of Rat Cerebral Cortex Exposed to Valproic Acid before Delivery

“…In other words, the VPA group was not as competent as the CON group in distinguishing between conspecifics and objects, and their social behaviors were less pronounced. − This indicates that the pups affected by VPA have difficulties in perception and recognition, which is similar to autism symptoms. As with other studies, − the results indicate that the VPA rat model of autism has been successfully established. Indeed, the autism VPA rat model, which was established in 2005, is a classic and ideal autism model .…”

“…These results were consistent with previous studies. − In behavioral experiments, the CON group was more inclined to favor strange rats, while the VPA group has a low tendency to favor conspecifics. In other words, the VPA group was not as competent as the CON group in distinguishing between conspecifics and objects, and their social behaviors were less pronounced. − This indicates that the pups affected by VPA have difficulties in perception and recognition, which is similar to autism symptoms. As with other studies, − the results indicate that the VPA rat model of autism has been successfully established.…”

Effects of arginine vasopressin on the transcriptome of prefrontal cortex in autistic rat model

“…This result is consistent with the transcriptome study of Zhang et al 36,37 Subsequently, we confirmed that synaptic development‐related genes SYN1 (Synapsin 1, a neuronal phosphoprotein involving in regulating axonogenesis and synaptogenesis 38 ) and SYNPO (synaptopodin, a marker and essential component of the dendritic spines 39 ) were significantly upregulated in autism, and significantly improved after AVP treatment. Consistently, Liu et al 40 found the Syn1 proteins relevant to synaptic plasticity in the PFC significantly increased in VPA‐induced autism model. Gomes 41 and Belagodu 42 et al also found the Syn1 proteins significantly increased in IL‐17 induced maternal immune activation model and Fragile X Syndrome model.…”

“…Consistently, Liu et al 40 signalling pathways, 43,44 and this pathway may influence the physiological and pathological functions of neuronal by ligand-receptor interactions in autism. 45,46 Calcium signalling is involved in many essential cellular functions and plays a key role in synaptic plasticity, neuron excitability, axon growth and neurotransmitter release and so on.…”

WDR62 deficiency results in synaptic dysfunction and ASD-like behaviors in mice, which can be ameliorated by RA repletion

“…Evidence from both human and animal studies indicate that RA homeostasis and RA signaling disruption are associated with ASD [16,17]. Therefore, Vitamin A or RA supplementation has been shown to alleviate social impairment in various animal models and children with ASD [16,[18][19][20]. Our previous studies indicate that WDR62 is required for RA-induced meiotic gene expression in germ cells [21].…”