Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, SE5 8AF, UK.
Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, De Crespigny Park, London, SE 5 8AF, UK.
Transl Psychiatry. 2022 Sep 20;12(1):395. doi: 10.1038/s41398-022-02143-1.
The metabotropic glutamate receptor 5 (mGluR5) is a key regulator of excitatory (E) glutamate and inhibitory (I) γ-amino butyric acid (GABA) signalling in the brain. Despite the close functional ties between mGluR5 and E/I signalling, no-one has directly examined the relationship between mGluR5 and glutamate or GABA in vivo in the human brain of autistic individuals. We measured [F] FPEB (F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile) binding in 15 adults (6 with Autism Spectrum Disorder) using two regions of interest, the left dorsomedial prefrontal cortex and a region primarily composed of left striatum and thalamus. These two regions were mapped out using MEGA-PRESS voxels and then superimposed on reconstructed PET images. This allowed for direct comparison between mGluR5, GABA + and Glx. To better understand the molecular underpinnings of our results we used an autoradiography study of mGluR5 in three mouse models associated with ASD: Cntnap2 knockout, Shank3 knockout, and 16p11.2 deletion. Autistic individuals had significantly higher [F] FPEB binding (t (13) = -2.86, p = 0.047) in the left striatum/thalamus region of interest as compared to controls. Within this region, there was a strong negative correlation between GABA + and mGluR5 density across the entire cohort (Pearson's correlation: r (14) = -0.763, p = 0.002). Cntnap2 KO mice had significantly higher mGlu5 receptor binding in the striatum (caudate-putamen) as compared to wild-type (WT) mice (n = 15, p = 0.03). There were no differences in mGluR5 binding for mice with the Shank3 knockout or 16p11.2 deletion. Given that Cntnap2 is associated with a specific striatal deficit of parvalbumin positive GABA interneurons and 'autistic' features, our findings suggest that an increase in mGluR5 in ASD may relate to GABAergic interneuron abnormalities.
代谢型谷氨酸受体 5（mGluR5）是大脑中兴奋性（E）谷氨酸和抑制性（I）γ-氨基丁酸（GABA）信号的关键调节剂。尽管 mGluR5 与 E/I 信号之间存在紧密的功能联系，但没有人直接在自闭症个体的人类大脑中检查 mGluR5 与谷氨酸或 GABA 之间的关系。我们使用两个感兴趣的区域（左侧背内侧前额叶皮层和主要由左侧纹状体和丘脑组成的区域），在 15 名成年人（6 名自闭症谱系障碍患者）中测量了 [F]FPEB（F-3-氟-5-[(吡啶-3-基)乙炔基]苯腈）的结合。这两个区域使用 MEGA-PRESS 体素绘制，并叠加在重建的 PET 图像上。这允许在 mGluR5、GABA+和 Glx 之间进行直接比较。为了更好地理解我们结果的分子基础，我们使用了与 ASD 相关的三种小鼠模型（Cntnap2 敲除、Shank3 敲除和 16p11.2 缺失）的 mGluR5 放射自显影研究。与对照组相比，自闭症个体在左侧纹状体/丘脑感兴趣区域的 [F]FPEB 结合显着增加（t（13）=-2.86，p=0.047）。在该区域，整个队列中 GABA+和 mGluR5 密度之间存在强烈的负相关（皮尔逊相关：r（14）=-0.763，p=0.002）。与野生型（WT）相比，Cntnap2 KO 小鼠的纹状体（尾状核-壳核）中的 mGlu5 受体结合显着增加（n=15，p=0.03）。Shank3 敲除或 16p11.2 缺失的小鼠的 mGluR5 结合没有差异。鉴于 Cntnap2 与特定的纹状体苍白球阳性 GABA 中间神经元缺陷和“自闭症”特征相关，我们的发现表明 ASD 中 mGluR5 的增加可能与 GABA 能中间神经元异常有关。
