Degraded cortical temporal processing in the valproic acid-induced rat model of autism

Honda

et al. 2022

J Neuroinflammation

Background Valproic acid (VPA) is a clinically used antiepileptic drug, but it is associated with a significant risk of a low verbal intelligence quotient (IQ) score, attention-deficit hyperactivity disorder and autism spectrum disorder in children when it is administered during pregnancy. Prenatal VPA exposure has been reported to affect neurogenesis and neuronal migration and differentiation. In addition, growing evidence has shown that microglia and brain immune cells are activated by VPA treatment. However, the role of VPA-activated microglia remains unclear. Methods Pregnant female mice received sodium valproate on E11.5. A microglial activation inhibitor, minocycline or a CCR5 antagonist, maraviroc was dissolved in drinking water and administered to dams from P1 to P21. Measurement of microglial activity, evaluation of neural circuit function and expression analysis were performed on P10. Behavioral tests were performed in the order of open field test, Y-maze test, social affiliation test and marble burying test from the age of 6 weeks. Results Prenatal exposure of mice to VPA induced microglial activation and neural circuit dysfunction in the CA1 region of the hippocampus during the early postnatal periods and post-developmental defects in working memory and social interaction and repetitive behaviors. Minocycline, a microglial activation inhibitor, clearly suppressed the above effects, suggesting that microglia elicit neural dysfunction and behavioral disorders. Next-generation sequencing analysis revealed that the expression of a chemokine, C–C motif chemokine ligand 3 (CCL3), was upregulated in the hippocampi of VPA-treated mice. CCL3 expression increased in microglia during the early postnatal periods via an epigenetic mechanism. The CCR5 antagonist maraviroc significantly suppressed neural circuit dysfunction and post-developmental behavioral disorders induced by prenatal VPA exposure. Conclusion These findings suggest that microglial CCL3 might act during development to contribute to VPA-induced post-developmental behavioral abnormalities. CCR5-targeting compounds such as maraviroc might alleviate behavioral disorders when administered early.

Section: Discussionmentioning

confidence: 93%

A CCR5 antagonist, maraviroc, alleviates neural circuit dysfunction and behavioral disorders induced by prenatal valproate exposure

Honda

et al. 2022

J Neuroinflammation

“…In the auditory cortex, the levels of GABA but not glutamate were increased in Pchd10 +/− mice [ 106 ]. However, in VPA rats, there are fewer inhibitory interneurons in the auditory cortex, while excitatory neurons have increased dendritic spine density [ 17 ]. The increased spine density could lead to hyperexcitability of responses to the same concentration of glutamate, but increased GABA with fewer inhibitory neurons seems unlikely, so it is unclear whether the phenotypes of these two models overlap.…”

Section: Resultsmentioning

confidence: 99%

“…This characteristic resembles the activity of A1 in younger WT rats, indicating this may represent an ‘immaturity’ of the auditory cortex in these animals [ 123 ]. VPA-treated rats also more poorly distinguish between different rates of sound stimulus presentation in behavioural tasks, which is likely linked to this electrophysiological finding [ 17 ]. Based on the results from the IC of Cacnα2δ3 −/− mice, this auditory cortex phenotype may arise subcortically [ 11 ].…”

Section: Resultsmentioning

confidence: 99%

“…The latency of responses is increased in A1 of Mecp2 +/− rats and Mecp2 overexpressing mice, and in the AAF of VPA rats, though it is decreased in the A1 of VPA rats and not affected at all in Shank3 −/− rats [4,28,32,33,152]. Speed of transmission likely also leads to the inability of auditory cortex neurons to follow along with rapidly presented sounds in Mecp2 +/− , Cntnap2 −/− , and VPA rats [17,32,123]. This characteristic resembles the activity of A1 in younger WT rats, indicating this may represent an 'immaturity' of the auditory cortex in these animals [123].…”

Section: Electrophysiologymentioning

confidence: 99%

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Auditory processing in rodent models of autism: a systematic review

Wilde

Constantin

Thorne

et al. 2022

J Neurodevelop Disord

Autism is a complex condition with many traits, including differences in auditory sensitivity. Studies in human autism are plagued by the difficulty of controlling for aetiology, whereas studies in individual rodent models cannot represent the full spectrum of human autism. This systematic review compares results in auditory studies across a wide range of established rodent models of autism to mimic the wide range of aetiologies in the human population. A search was conducted in the PubMed and Web of Science databases to find primary research articles in mouse or rat models of autism which investigate central auditory processing. A total of 88 studies were included. These used non-invasive measures of auditory function, such as auditory brainstem response recordings, cortical event-related potentials, electroencephalography, and behavioural tests, which are translatable to human studies. They also included invasive measures, such as electrophysiology and histology, which shed insight on the origins of the phenotypes found in the non-invasive studies. The most consistent results across these studies were increased latency of the N1 peak of event-related potentials, decreased power and coherence of gamma activity in the auditory cortex, and increased auditory startle responses to high sound levels. Invasive studies indicated loss of subcortical inhibitory neurons, hyperactivity in the lateral superior olive and auditory thalamus, and reduced specificity of responses in the auditory cortex. This review compares the auditory phenotypes across rodent models and highlights those that mimic findings in human studies, providing a framework and avenues for future studies to inform understanding of the auditory system in autism.

“…The ring rate from all 6 bursts was quanti ed by taking the average number of driven spikes. Vector strength was used to quantify the synchrony of the noise bursts [25]. For all analysis, normal distributions were determined using the Lilliefors Test for Normality.…”

Section: Discussionmentioning

confidence: 99%

Degraded inferior colliculus responses to complex sounds in prenatally exposed VPA rats

Tamaoki,

Pasapula,

Chandler

et al. 2023

Preprint

Background Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. Methods Neural recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. Results Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared saline-exposed controls, but responses to tones and noise burst trains were unaltered. Conclusions These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.