Department of Biology, James Madison University, 951 Carrier Drive, Harrisonburg, VA, 22807, USA.
BMC Neurosci. 2022 Mar 5;23(1):12. doi: 10.1186/s12868-022-00691-2.
Autism spectrum disorder (ASD) is characterized by repetitive behaviors, deficits in communication, and overall impaired social interaction. Of all the integrin subunit mutations, mutations in integrin β3 (Itgb3) may be the most closely associated with ASD. Integrin β3 is required for normal structural plasticity of dendrites and synapses specifically in excitatory cortical and hippocampal circuitry. However, the behavioral consequences of Itgb3 function in the forebrain have not been assessed. We tested the hypothesis that behaviors that are typically abnormal in ASD-such as self-grooming and sociability behaviors-are disrupted with conditional Itgb3 loss of function in forebrain circuitry in male and female mice.
We generated male and female conditional knockouts (cKO) and conditional heterozygotes (cHET) of Itgb3 in excitatory neurons and glia that were derived from Emx1-expressing forebrain cells during development. We used several different assays to determine whether male and female cKO and cHET mice have repetitive self-grooming behaviors, anxiety-like behaviors, abnormal locomotion, compulsive-like behaviors, or abnormal social behaviors, when compared to male and female wildtype (WT) mice.
Our findings indicate that only self-grooming and sociability are altered in cKO, but not cHET or WT mice, suggesting that Itgb3 is specifically required in forebrain Emx1-expressing cells for normal repetitive self-grooming and social behaviors. Furthermore, in cKO (but not cHET or WT), we observed an interaction effect for sex and self-grooming environment and an interaction effect for sex and sociability test chamber.
While this study demonstrated a role for forebrain Itgb3 in specific repetitive and social behaviors, it was unable to determine whether forebrain Itgb3 is required for a preference for social novelty, whether cHET are haploinsufficient with respect to repetitive self-grooming and social behaviors, or the nature of the interaction effect for sex and environment/chamber in affected behaviors of cKO.
Together, these findings strengthen the idea that Itgb3 has a specific role in shaping forebrain circuitry that is relevant to endophenotypes of autism spectrum disorder.
自闭症谱系障碍（ASD）的特征是重复行为、沟通缺陷以及整体社交互动受损。在所有整合素亚基突变中，整合素β3（Itgb3）的突变可能与 ASD 最为密切相关。整合素β3是兴奋性皮质和海马回路中树突和突触正常结构可塑性所必需的。然而，Itgb3 在前脑中的功能的行为后果尚未得到评估。我们测试了这样一个假设，即 ASD 中通常异常的行为，如自我修饰和社交行为，会因前脑电路中 Itgb3 功能的条件缺失而中断，在雄性和雌性小鼠中。
我们在发育过程中从 Emx1 表达的前脑细胞中产生了雄性和雌性条件敲除（cKO）和条件杂合子（cHET）的 Itgb3，以敲除兴奋性神经元和神经胶质中的 Itgb3。我们使用了几种不同的测定方法来确定雄性和雌性 cKO 和 cHET 小鼠是否具有重复的自我修饰行为、焦虑样行为、异常运动、强迫样行为或异常社交行为，与雄性和雌性野生型（WT）小鼠相比。
我们的研究结果表明，只有自我修饰和社交行为在 cKO 中发生改变，而在 cHET 或 WT 小鼠中则没有，这表明 Itgb3 在前脑 Emx1 表达细胞中对于正常的重复自我修饰和社交行为是特异性需要的。此外，在 cKO（但不是 cHET 或 WT）中，我们观察到性和自我修饰环境之间的交互作用以及性和社交测试室之间的交互作用。
虽然这项研究表明前脑 Itgb3 在特定的重复和社交行为中发挥了作用，但它无法确定前脑 Itgb3 是否需要对社交新奇性有偏好，cHET 是否在重复自我修饰和社交行为方面存在单倍不足，或者性和环境/室在受影响的 cKO 行为中的相互作用效应的性质。
综上所述，这些发现加强了这样一种观点，即 Itgb3 在塑造与自闭症谱系障碍的表型相关的前脑回路方面具有特定的作用。
