Functional consequences of in vivo ablation of NG2 cells

描述(申请人提供)：哺乳动物中枢神经系统含有大量广泛分布的神经胶质前体细胞，称为NG2细胞(也称为少突胶质前体细胞或多树突状细胞)，它们具有发育成少突胶质细胞的能力，并在损伤和脱髓鞘时发生显著变化。尽管这些细胞保留了在成人大脑和脊髓中生成少突胶质细胞的能力，但成人中枢神经系统中的大多数NG2细胞不分化，仍处于“祖细胞”状态。NG2细胞在所有的灰质和白质区域以网格状的方式排列，将高度分叉的突起延伸到周围的神经纤维，并与神经元形成直接突触，这增加了它们调节神经元活动和信息通过神经回路流动的可能性。此外，NG2细胞在急性和慢性损伤中增殖，增加NG2的表达，并有助于胶质瘢痕的形成，这表明它们可能有助于限制神经退行性变和促进修复。然而，我们对这些丰富的神经胶质细胞的作用以及它们在缺血损伤后行为改变的后果的了解非常有限。为了确定NG2细胞在成人大脑中的功能，我们最近开发了转基因小鼠，允许在体内选择性地消融NG2细胞。利用这些小鼠，NG2细胞可以从大脑中移除，而不会导致星形胶质细胞或小胶质细胞的反应性变化，也不会导致瘫痪或死亡，这表明这种方法可以帮助确定这些无处不在的胶质细胞的功能。在拟议的研究中，我们将在体内选择性地消融中枢神经系统中的NG2细胞，并检查它们的缺失是否会导致神经元活动、突触信号、轴突传导或特定行为方面的变化，如空间记忆、焦虑或感觉运动控制。此外，我们还将研究移除NG2细胞是否会改变其他神经胶质细胞对局灶性脑缺血的反应以及神经元损伤的程度。总之，这些探索性研究有可能揭示这一神秘的神经胶质细胞群体在成人大脑中的新角色，并加深我们对神经元和神经胶质细胞在生理和病理条件下发生相互作用的理解。如果NG2细胞参与神经调节和中枢神经系统修复，它们将是一个额外的治疗靶点，有可能减少异常神经元活动，防止慢性病中的神经变性，并促进中风后的恢复和修复。 公共卫生相关性：这项建议试图确定成人中枢神经系统中丰富、广泛分布的神经胶质细胞群是否影响通过神经回路的信息流，并促进缺血后的修复。这些研究有可能发现调节异常神经元活动的新途径，以及减少中风后的损伤和加速康复。

DESCRIPTION (provided by applicant): The mammalian CNS contains an abundant, widely distributed population of glial progenitors known as NG2 cells (also termed oligodendrocyte precursor cells or polydendrocytes) that have the ability to develop into oligodendrocytes and undergo dramatic changes in response to injury and demyelination. Although these cells retain the capacity to generate oligodendrocytes in the adult brain and spinal cord, most NG2 cells in the adult CNS do not differentiate and remain in a "progenitor" state. NG2 cells are arranged in a grid-like manner in all gray and white matter regions, extend highly ramified processes into the surrounding neuropil, and form direct synapses with neurons, raising the possibility that they modulate the activity of neurons and the flow of information through neural circuits. Moreover, NG2 cells proliferate, increase expression of NG2, and contribute to the formation of glial scars in response to both acute and chronic injury, suggesting that they may help limit neurodegeneration and promote repair. Nevertheless, our knowledge about the roles of these abundant glial cells, and the consequences of their change in behavior following ischemic injury, is very limited. To define the functions of NG2 cells in the adult brain, we recently developed transgenic mice that allow selective ablation of NG2 cells in vivo. Using these mice, NG2 cells can be removed from the brain without inducing reactive changes in astrocytes or microglial cells, or causing paralysis or death, indicating that this approach can be used to help define the functions of these ubiquitous glial cells. In the proposed studies, we will selectively ablate NG2 cells from the CNS in vivo, and examine whether their absence results in alterations in neuronal activity, signaling at synapses, axonal conduction, or specific aspects of behavior, such as spatial memory, anxiety, or sensorimotor control. In addition, we will examine whether removal of NG2 cells alters the response of other glial cells to focal ischemia and the extent of neuronal injury. Together, these exploratory studies have the potential to reveal new roles for this enigmatic population of glial cells in the adult brain, and deepen our understanding of interactions that occur between neurons and glial cells in physiological and pathological conditions. If NG2 cells participate in neuromodulation and CNS repair, they would represent an additional therapeutic target with the potential to reduce abnormal neuronal activity, prevent neurodegeneration in chronic disease, and promote recovery and repair following stroke. PUBLIC HEALTH RELEVANCE: This proposal seeks to determine whether an abundant, widely distributed population of glial cells in adult CNS influences the flow of information through neural circuits and promotes repair following ischemia. These studies have the potential to identify new pathways for regulating abnormal neuronal activity, as well as reducing injury and accelerating recovery after stroke.