Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder

Ana Belen Lopez-Rodriguez, Carol L. Murray, John Kealy, Clodagh Towns, Andrew Roche, Arshed Nazmi, Michelle Doran, John P. Lowry & Colm Cunningham

Background

Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD.

Methods

We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 µg/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal–Wallis or Mann–Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p < 0.05. For correlation analyses, data were adjusted by a linear regression model.

Results

Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5–48 h.

Limitations

We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements.

Conclusions

The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits.

自闭症谱系障碍（ASD）主要是神经发育性疾病，而且在很大程度上是由基因决定的。然而，有数据支持发烧可以改善某些人的症状这一观点，但这些数据是有限的，而且几乎没有动物模型的数据支持这一观点。我们旨在验证体温升高可改善两种 ASD 动物模型功能的假设。

实验方法

我们使用 4 小时全身热疗（WBH）方案，并分别使用 250 微克/千克细菌内毒素（LPS）诱导的全身炎症，来区分两种 ASD 动物模型的体温和发热的炎症因素： C58/J和Shank3B-小鼠。对于正态分布的数据，我们使用了单因子或双因子方差分析和 t 检验；对于非参数数据，我们使用了 Kruskal-Wallis 或 Mann-Whitney 检验。事后比较的显著性水平设定为 p < 0.05。对于相关性分析，数据通过线性回归模型进行调整。

研究结果

只有 LPS 能诱发大脑炎症特征，而只有 WBH 能产生发热范围的高热。WBH 可减少 C58/J 小鼠的重复行为，改善其社会交往，并显著减少 Shank3B- 小鼠的强迫性梳理行为。LPS 在 5-48 小时内明显抑制了大多数活动。

局限性

我们展示了行为、细胞和分子变化，但没有对观察到的行为改善提供具体的机理解释。

研究结论

据我们所知，这些数据首次证明体温升高可以改善两个不同的 ASD 模型的行为体征。鉴于自闭症的发育性质，环境干扰可改善症状的证据表明，有可能改善这些人的功能。由于在患者身上进行实验性热疗会有很大风险，因此现在有必要研究热疗可能带来所观察到的益处的分子机制。