title: Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications.
abstract: Metabotropic glutamate receptor 5 (mGluR5) and microglial abnormalities have been implicated in autism spectrum disorder (ASD). However, controversy exists as to whether the receptor is down or upregulated in functioning in ASD. In addition, whilst activation of mGluR5 has been shown to attenuate microglial activation, its role in maintaining microglial homeostasis during development has not been investigated. We utilised published microarray data from the dorsolateral prefrontal cortex (DLPFC) of control (n=30) and ASD (n=27) individuals to carry out regression analysis to assess gene expression of mGluR5 downstream signalling elements. We then conducted a post-mortem brain stereological investigation of the DLPFC, to estimate the proportion of mGluR5-positive neurons and glia. Finally, we carried out stereological investigation into numbers of microglia in mGluR5 knockout mice, relative to wildtype littermates, together with assessment of changes in microglial somal size, as an indicator of activation status. We found that gene expression of mGluR5 was significantly decreased in ASD versus controls (p=0.018) as well as downstream elements SHANK3 (p=0.005) and PLCB1 (p=0.009) but that the pro-inflammatory marker NOS2 was increased (p=0.047). Intensity of staining of mGluR5-positive neurons was also significantly decreased in ASD versus controls (p=0.016). Microglial density was significantly increased in mGluR5 knockout animals versus wildtype controls (p=0.011). Our findings provide evidence for decreased expression of mGluR5 and its signalling components representing a key pathophysiological hallmark in ASD with implications for the regulation of microglial number and activation during development. This is important in the context of microglia being considered to play key roles in synaptic pruning during development, with preservation of appropriate connectivity relevant for normal brain functioning.
authors.affiliation: Centre for Neural Engineering, The University of Melbourne, Parkville, Victoria, Australia; Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: gchana@unimelb.edu.au.
authors.forename: Gursharan
authors.initials: G
authors.lastname: Chana
authors.affiliation: Centre for Neural Engineering, The University of Melbourne, Parkville, Victoria, Australia; Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Liliana
authors.initials: L
authors.lastname: Laskaris
authors.affiliation: Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia; Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Parkville, Victoria, Australia.
authors.forename: Christos
authors.initials: C
authors.lastname: Pantelis
authors.affiliation: Centre for Neural Engineering, The University of Melbourne, Parkville, Victoria, Australia; Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Piers
authors.initials: P
authors.lastname: Gillett
authors.affiliation: Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Parkville, Victoria, Australia; Department of Psychology, Monash University, Clayton, Victoria, Australia.
authors.forename: Renee
authors.initials: R
authors.lastname: Testa
authors.affiliation: Department of Haematology, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Zantomio
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne Parkville, Victoria, Australia.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Burrows
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne Parkville, Victoria, Australia; Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Hannan
authors.affiliation: Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Everall
authors.affiliation: Centre for Neural Engineering, The University of Melbourne, Parkville, Victoria, Australia; Department of Psychiatry, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Efstratios
authors.initials: E
authors.lastname: Skafidas
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*
chemical_list: C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5
keywords: Autism; Glutamate; Microglia; Neuroinflammation; Neuropathology; Stereology