Lateralized change in cortical neural networks in autism spectrum disorders

项目总结 大脑结构和功能的异常偏侧化与神经发育障碍有关 自闭症谱系障碍(ASD)。我们最近报告了偏侧性减少的数量。 小白蛋白表达(PV+)篮子细胞(BCS)在L2/3的躯体感觉皮质占优势 成年Shank3/-小鼠ASD模型大脑半球。优势半球由一个 完成任务，定义每种动物的优势前爪。我们进一步使用了一个标记来识别 将特定的细胞外基质包裹BCs，发现BCs的数量与 这两个半球，但更确切地说，一些BCS不表达可检测的PV水平(PV-BCS)。值得注意的是， 我们发现，优势足的机械过敏反应与 相应皮质中PV+BC的数量。然而，几乎什么都不知道关于 BCS中观察到的偏侧化的发展轨迹和PV减少的影响 BCS或锥体神经元特性在局部神经回路中的表达。在本提案中， 我们将首先在L2/3中表征BC-锥体细胞网络属性的半球间差异 结合体内钙(Ca~(2+))成像研究Shank3-/-小鼠的体感皮层 晶须刺激和体外膜片钳记录。我们调查活动中的差异，并 在Shank3-/-小鼠中存在PV+BCS和非典型PV-BCS的电生理特性。接下来，我们将 用体内L2/3锥体细胞钙显像法评价躯体感觉皮层输出的变化 在Shank3-/-小鼠刺激胡须的过程中，桶状皮质中。此外，为了确定激励 /抑制比，我们将使用膜片钳记录来研究L2/3锥体的突触输入 细胞在电刺激L4的过程中。最后，我们将确定 大鼠躯体感觉皮质L2/3PV+和PV-BCS数目的半球差异 SHANK3-/-小鼠进行免疫组织化学染色。免疫组织化学、电生理学检测结果 这里提出的钙成像研究将显著增加我们对血管紧张素转换酶的作用的了解 在ASD的病理生理学中优势半球的偏侧化改变，并可能提供 为新的治疗方法提供手段。

Project summary Aberrant lateralization in brain structure and function is linked to the neurodevelopmental disorders such as autism spectrum disorders (ASD). We have recently reported a lateralized decrease in the number of parvalbumin expressing (PV+) basket cells (BCs) in L2/3 of the somatosensory cortex in the dominant hemisphere of adult Shank3-/- mouse model of ASD. The dominant hemisphere was identified by a reaching task to define each animal’s dominant forepaw. We further used a marker to recognize the specific extracellular matrix enwrapping BCs and found that the number of BCs was not different between the two hemispheres, but rather, some BCs did not express detectable levels of PV (PV- BCs). Remarkably, we showed a mechanical hypersensitivity in the dominant paw correlated with the decrease in the number of PV+ BCs in the corresponding cortex. However, almost nothing is known regarding the developmental trajectory of the observed lateralization in BCs and the impact of a reduction in PV expression on the properties of BCs or pyramidal neurons in local neural circuits. In the present proposal, we will first characterize interhemispheric differences in BC – pyramidal cell network properties in L2/3 of the somatosensory cortex in the Shank3-/- mouse by a combination of in vivo calcium (Ca2+) imaging during whisker stimulation and in vitro patch clamp recording. We investigate differences in the activity and electrophysiological properties of PV+ BCs and the atypical PV- BCs present in Shank3-/- mice. Next, we will evaluate changes in the output of the somatosensory cortex by in vivo Ca2+ imaging of L2/3 pyramidal cells in the barrel cortex during whisker stimulation in Shank3-/- mice. Furthermore, to determine the excitation / inhibition ratio directly, we will use patch clamp recording to study the synaptic inputs to L2/3 pyramidal cells during electrical stimulation of L4. Finally, we will identify the developmental trajectory of interhemispheric differences in the number of L2/3 PV+ and PV- BCs in the somatosensory cortex of the Shank3-/- mouse using immunohistochemistry. Results of the immunohistochemistry, electrophysiology and calcium imaging studies proposed here will significantly increase our knowledge about the role of lateralized changes in the dominant hemisphere in the pathophysiology of ASD and could provide the means for new therapeutic approaches.