Altered sensory information processing, and auditory processing, in particular, is a common impairment in individuals with autism spectrum disorder (ASD). One prominent hypothesis for the etiology of ASD is an imbalance between neuronal excitation and inhibition. The selective GABAB receptor agonist R-Baclofen has been shown previously to improve social deficits and repetitive behaviors in several mouse models for neurodevelopmental disorders including ASD, and its formulation Arbaclofen has been shown to ameliorate social avoidance symptoms in some individuals with ASD. The present study investigated whether R-Baclofen can remediate ASD-related altered sensory processing reliant on excitation/inhibition imbalance in the auditory brainstem. To assess a possible excitation/inhibition imbalance in the startle-mediating brainstem underlying ASD-like auditory-evoked behaviors, we detected and quantified brain amino acid levels in the nucleus reticularis pontis caudalis (PnC) of rats with a homozygous loss-of-function mutation in the ASD-linked gene Contactin-associated protein-like 2 (Cntnap2) and their wildtype (WT) littermates using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry (MALDI MS). Abnormal behavioral read-outs of brainstem auditory signaling in Cntnap2 KO rats were accompanied by increased levels of GABA, glutamate, and glutamine in the PnC. We then compared the effect of R-Baclofen on behavioral read-outs of brainstem auditory signaling in Cntnap2 KO and WT rats. Auditory reactivity, sensory filtering, and sensorimotor gating were tested in form of acoustic startle response input-output functions, short-term habituation, and prepulse inhibition before and after acute administration of R-Baclofen (0.75, 1.5, and 3 mg/kg). Systemic R-Baclofen treatment improved disruptions in sensory filtering in Cntnap2 KO rats and suppressed exaggerated auditory startle responses, in particular to moderately loud sounds. Lower ASR thresholds in Cntnap2 KO rats were increased in a dose-dependent fashion, with the two higher doses bringing thresholds close to controls, whereas shorter ASR peak latencies at the threshold were further exacerbated. Impaired prepulse inhibition increased across various acoustic prepulse conditions after administration of R-Baclofen in Cntnap2 KO rats, whereas R-Baclofen did not affect prepulse inhibition in WT rats. Our findings suggest that GABAB receptor agonists may be useful for pharmacologically targeting multiple aspects of sensory processing disruptions involving neuronal excitation/inhibition imbalances in ASD.

中文翻译：

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GABAB 受体激动剂 R-巴氯芬逆转 Cntnap2 敲除大鼠的听觉反应性和过滤改变。

改变感觉信息处理，尤其是听觉处理，是自闭症谱系障碍 (ASD) 患者的常见障碍。ASD 病因的一个突出假设是神经元兴奋和抑制之间的不平衡。先前已证明选择性 GABAB 受体激动剂 R-巴氯芬可改善包括 ASD 在内的多种神经发育障碍小鼠模型的社交缺陷和重复行为，其制剂 Arbaclofen 已被证明可改善某些 ASD 患者的社交回避症状。本研究调查了 R-巴氯芬是否可以修复依赖于听觉脑干兴奋/抑制失衡的 ASD 相关感觉处理改变。为了评估 ASD 样听觉诱发行为背后的惊吓介导脑干中可能的兴奋/抑制失衡，我们检测并量化了具有纯合子功能丧失的大鼠的网状核 (PnC) 中的脑氨基酸水平使用基质辅助激光解吸电离质谱 (MALDI MS) 在 ASD 相关基因 Contactin 相关蛋白样 2 (Cntnap2) 及其野生型 (WT) 同窝仔中发生突变。Cntnap2 KO 大鼠脑干听觉信号的异常行为读数伴随着 PnC 中 GABA、谷氨酸和谷氨酰胺水平的增加。然后，我们比较了 R-巴氯芬对 Cntnap2 KO 和 WT 大鼠脑干听觉信号行为读数的影响。听觉反应，感觉过滤，在急性施用 R-巴氯芬（0.75、1.5 和 3 mg/kg）之前和之后，以听觉惊吓反应输入-输出功能、短期习惯和前脉冲抑制的形式测试和感觉运动门控。全身性 R-巴氯芬治疗改善了 Cntnap2 KO 大鼠感觉过滤的中断，并抑制了夸张的听觉惊吓反应，特别是对中等响亮的声音。Cntnap2 KO 大鼠的较低 ASR 阈值以剂量依赖性方式增加，两个较高剂量使阈值接近对照，而阈值处较短的 ASR 峰值延迟进一步加剧。在 Cntnap2 KO 大鼠中施用 R-巴氯芬后，在各种声学前脉冲条件下，受损的前脉冲抑制增加，而 R-巴氯芬不影响 WT 大鼠的前脉冲抑制。