From bench to bedside: The mGluR5 system in people with and without Autism Spectrum Disorder and animal model systems
| Autor: | Cornelia Carey, Nisha Singh, Joel T. Dunn, Teresa Sementa, Maria Andreina Mendez, Hester Velthuis, Andreia C. Pereira, Charlotte Marie Pretzsch, Jamie Horder, Stefan Hader, David J. Lythgoe, Diana-Georgina Rotaru, Anthony Gee, Diana Cash, Mattia Veronese, Declan Murphy, Grainne McAlonan |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Autism Spectrum Disorder Receptor Metabotropic Glutamate 5 Microfilament Proteins Glutamic Acid Membrane Proteins Nerve Tissue Proteins Cellular and Molecular Neuroscience Psychiatry and Mental health Disease Models Animal Mice Parvalbumins Animals Humans Biological Psychiatry gamma-Aminobutyric Acid |
| Zdroj: | Translational psychiatry. 12(1) |
| ISSN: | 2158-3188 |
| Popis: | 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 [18F] FPEB (18F-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 [18F] 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. |
| Databáze: | OpenAIRE |
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