National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore 560065, India.
School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur 613401, India.
eNeuro. 2021 Oct 8;8(5). doi: 10.1523/ENEURO.0493-20.2021. Print 2021 Sep-Oct.
Autism spectrum disorders (ASDs) are characterized by abnormal behavioral traits arising from neural circuit dysfunction. While a number of genes have been implicated in ASDs, in most cases, a clear understanding of how mutations in these genes lead to circuit dysfunction and behavioral abnormality is absent. The () gene is one such gene, associated with ASDs, intellectual disability and a range of other neurodevelopmental conditions. However, the role of AUTS2 in neural development and circuit function is not at all known. Here, we undertook functional analysis of Auts2a, the main homolog of AUTS2 in zebrafish, in the context of the escape behavior. Escape behavior in wild-type zebrafish is critical for survival and is therefore, reliable, rapid, and has well-defined kinematic properties. mutant zebrafish are viable, have normal gross morphology and can generate escape behavior with normal kinematics. However, the behavior is unreliable and delayed, with high trial-to-trial variability in the latency. Using calcium imaging we probed the activity of Mauthner neurons during otic vesicle (OV) stimulation and observed lower probability of activation and reduced calcium transients in the mutants. With direct activation of Mauthner by antidromic stimulation, the threshold for activation in mutants was higher than that in wild-type, even when inhibition was blocked. Taken together, these results point to reduced excitability of Mauthner neurons in mutant larvae leading to unreliable escape responses. Our results show a novel role for Auts2a in regulating neural excitability and reliability of behavior.
自闭症谱系障碍（ASD）的特征是神经回路功能障碍导致的异常行为特征。虽然有许多基因与 ASDs 有关，但在大多数情况下，这些基因的突变如何导致回路功能障碍和行为异常尚不清楚。AUTS2 基因就是这样一个与 ASDs、智力障碍和一系列其他神经发育状况相关的基因。然而，A UTS2 在神经发育和回路功能中的作用尚不清楚。在这里，我们在逃避行为的背景下对斑马鱼中 AUTS2 的主要同源物 Auts2a 进行了功能分析。野生型斑马鱼的逃避行为对生存至关重要，因此是可靠的、快速的，并且具有明确的运动学特征。mutant 斑马鱼具有活力，其大体形态正常，并且可以产生具有正常运动学的逃避行为。然而，行为不可靠且延迟，潜伏期的试验间变异性很高。我们使用钙成像技术在卵囊（OV）刺激期间探测 Mauthner 神经元的活动，观察到突变体中的激活概率较低，钙瞬变减少。通过逆行刺激对 Mauthner 的直接激活，突变体中的激活阈值高于野生型，即使抑制被阻断也是如此。总之，这些结果表明突变体幼虫中的 Mauthner 神经元兴奋性降低，导致逃避反应不可靠。我们的研究结果表明 Auts2a 在调节神经兴奋性和行为可靠性方面具有新的作用。
