Lateralized change in cortical neural networks in shank3 mutant mice

shank3突变小鼠皮质神经网络的侧化变化

• 批准号: 10450250
• 负责人: Tara Deemyad
• 金额: $ 7.92万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2022-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450250
• 关键词: Address; Adult; Affect; Age; Animals; Behavior; Behavioral; Brain; Buffers; Calcium; Cerebral Dominance; Cerebral cortex; Characteristics; Defect; Development; Electric Stimulation; Electrophysiology (science); Equilibrium; Exhibits; Extracellular Matrix; Functional disorder; Future; Human; Hyperactivity; Hypersensitivity; Image; Immunohistochemistry; In Vitro; Knowledge; Label; Language Development; Lead; Lectin; Link; Maintenance; Measures; Mechanics; Methods; Movement; Mus; Mutant Strains Mice; Myoepithelial cell; Neurodevelopmental Disorder; Neurologic; Neurons; Output; Parvalbumins; Pattern; Play; Population; Property; Pyramidal Cells; Reporting; Role; Sensory; Side; Social Behavior; Somatosensory Cortex; Structure; Synapses; Time; Vibrissae; Vicia; Viral; autism spectrum disorder; barrel cortex; cognitive process; critical period; experimental study; hippocampal pyramidal neuron; imaging study; in vivo; in vivo calcium imaging; individuals with autism spectrum disorder; interdisciplinary approach; learned behavior; mouse model; neural circuit; neural network; novel; novel therapeutic intervention; patch clamp; postnatal period; response; risk variant; targeted treatment

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.

项目摘要 大脑结构和功能的异常偏侧与神经发育障碍有关，例如 自闭症谱系障碍（ASD）。我们最近报道了一个偏侧减少的数量， L2/3躯体感觉皮层中的小清蛋白表达（PV+）篮细胞（BC）在显性 ASD成年Shank 3-/-小鼠模型的半球。优势半球由一个 来确定每只动物的主要前爪。我们进一步使用标记来识别 特异性细胞外基质包裹BCs，并发现BCs的数量在 相反，一些BCs不表达可检测水平的PV（PV-BCs）。值得注意的是， 我们发现在优势爪中的机械超敏性与 相应皮质中PV+ BC的数量。然而，几乎没有什么是已知的， 观察到的BC偏侧化的发展轨迹和PV减少的影响 在局部神经回路中的BC或锥体神经元的性质的表达。在本提案中， 我们将首先描述大脑半球间BC -锥体细胞网络特性的差异， 在Shank 3-/-小鼠中，通过结合体内钙（Ca 2+）成像， 晶须刺激和体外膜片钳记录。我们调查了活动的差异， PV+ BCs和Shank 3-/-小鼠中存在的非典型PV-BCs的电生理特性。接下来我们就 通过L2/3锥体细胞的体内Ca 2+成像评估体感皮层输出的变化 在Shank 3-/-小鼠的触须刺激过程中，此外，为了确定激励 /抑制比，我们将用膜片钳记录来研究L2/3锥体的突触输入 L4的电刺激期间的细胞。最后，我们将确定的发展轨迹， L2/3 PV+和PV-BCs在躯体感觉皮层中的数量存在半球间差异。 Shank 3-/-小鼠使用免疫组织化学。免疫组织化学，电生理学 钙成像研究将大大增加我们的知识的作用， 在ASD的病理生理学优势半球的偏侧化变化，并可以提供 新的治疗方法。