Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain.
Unidad Clínica de Neurociencias, Hospital Regional Universitario de Málaga, Málaga, Spain.
Brain Struct Funct. 2021 Jun;226(5):1479-1495. doi: 10.1007/s00429-021-02261-4. Epub 2021 Apr 1.
Defects in GABAergic function can cause anxiety- and depression-like behaviors among other neuropsychiatric disorders. Therapeutic strategies using the transplantation of GABAergic interneuron progenitors derived from the medial ganglionic eminence (MGE) into the adult hippocampus reversed the symptomatology in multiple rodent models of interneuron-related pathologies. In turn, the lysophosphatidic acid receptor LPA has been reported to be essential for hippocampal function. Converging evidence suggests that deficits in LPA receptor signaling represent a core feature underlying comparable hippocampal dysfunction and behaviors manifested in common neuropsychiatric conditions. Here, we first analyzed the GABAergic interneurons in the hippocampus of wild-type and maLPA-null mice, lacking the LPA receptor. Our data revealed a reduction in the number of neurons expressing GABA, calcium-binding proteins, and neuropeptides such as somatostatin and neuropeptide Y in the hippocampus of maLPA-null mice. Then, we used interneuron precursor transplants to test links between hippocampal GABAergic interneuron deficit, cell-based therapy, and LPA receptor-dependent psychiatric disease-like phenotypes. For this purpose, we transplanted MGE-derived interneuron precursors into the adult hippocampus of maLPA-null mice, to test their effects on GABAergic deficit and behavioral symptoms associated with the absence of the LPA receptor. Transplant studies in maLPA-null mice showed that grafted cells were able to restore the hippocampal host environment, decrease the anxiety-like behaviors and neutralize passive coping, with no abnormal effects on motor activity. Furthermore, grafted MGE-derived cells maintained their normal differentiation program. These findings reinforce the use of cell-based strategies for brain disorders and suggest that the LPA receptor represents a potential target for interneuron-related neuropsychiatric disorders.
GABA 能功能障碍可导致焦虑和抑郁样行为以及其他神经精神疾病。使用源自内侧神经节隆起（MGE）的 GABA 能中间神经元祖细胞移植到成年海马体的治疗策略，逆转了多种与中间神经元相关病理的啮齿动物模型中的症状。反过来，溶血磷脂酸受体 LPA 已被报道对海马体功能至关重要。越来越多的证据表明，LPA 受体信号传导的缺陷代表了共同神经精神疾病中表现出的类似海马体功能障碍和行为的核心特征。在这里，我们首先分析了野生型和 maLPA 敲除小鼠海马体中的 GABA 能中间神经元，这些小鼠缺乏 LPA 受体。我们的数据显示，maLPA 敲除小鼠海马体中表达 GABA、钙结合蛋白和神经肽（如生长抑素和神经肽 Y）的神经元数量减少。然后，我们使用中间神经元前体移植来测试海马体 GABA 能中间神经元缺陷、基于细胞的治疗与 LPA 受体依赖性精神疾病样表型之间的联系。为此，我们将 MGE 衍生的中间神经元前体移植到 maLPA 敲除小鼠的成年海马体中，以测试它们对 GABA 能缺陷和与缺乏 LPA 受体相关的行为症状的影响。在 maLPA 敲除小鼠中的移植研究表明，移植的细胞能够恢复海马体宿主环境，降低焦虑样行为并中和被动应对，而对运动活动没有异常影响。此外，移植的 MGE 衍生细胞保持其正常的分化程序。这些发现加强了基于细胞的策略在脑疾病中的应用，并表明 LPA 受体代表了与中间神经元相关的神经精神疾病的潜在靶点。
