Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice

Abstract

Autism spectrum disorder (ASD) is characterized by dysfunction in social interactions, stereotypical behaviours and high co-morbidity with intellectual disability. A variety of syndromic and non-syndromic neurodevelopmental disorders have been connected to alterations in metabotropic glutamate receptor (mGluR) signalling. These receptors contribute to synaptic plasticity, spine maturation and circuit development. Here, we investigate the physiological role of Gprasp2 , a gene linked to neurodevelopmental disabilities and involved in the postendocytic sorting of G-protein-coupled receptors. We show that Gprasp2 deletion leads to ASD-like behaviour in mice and alterations in synaptic communication. Manipulating the levels of Gprasp2 bidirectionally modulates the surface availability of mGluR 5 and produces alterations in dendritic complexity, spine density and synaptic maturation. Loss of Gprasp2 leads to enhanced hippocampal long-term depression, consistent with facilitated mGluR-dependent activation. These findings demonstrate a role for Gprasp2 in glutamatergic synapses and suggest a possible mechanism by which this gene is linked to neurodevelopmental diseases.

Hyperactivated PTP1B phosphatase in parvalbumin neurons alters anterior cingulate inhibitory circuits and induces autism-like behaviors

“…mGluR5 function may be similarly affected in PV-Lmo4KO mice. Altered mGluR5 function has been associated with autism-like behaviors in mice lacking Gprasp2 43 . Moreover, PV neuron-specific ablation of mGluR5 induces social novelty deficits and compulsive repetitive behaviors associated with loss of PV neurons and reduced inhibitory currents (mIPSC) at the hippocampus 44 .…”

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

“…Studies in humans and animal models have revealed aberrations in dendritic spine architecture in several psychiatric disorders including depression and others related to stress (Edfawy et al, 2019;Guo et al, 2019;Yang et al, 2020). Changes in spine density and organization are thought to contribute to the behavioral disorder caused by stress exposure (Chen et al, 2020).…”

Social subordination induced by early life adversity rewires inhibitory control of the prefrontal cortex via enhanced Npy1r signaling

“…Detailed methods for behavioral tests, electrophysiology recordings, neuronal labeling with AAV, and confocal imaging, preparation of RNA and DNA samples, RNAseq, methylation assays, qRT-PCR, immunofluorescence, and tissue dissection methodologies were performed as previously described [ 17 – 19 ] and are provided as Supplementary materials and methods .…”

“…We chose to investigate the mPFC since this region is: (1) strongly targeted by the glucocorticoid system [8], (2) responsible for top-down control of other brain systems according to the animals' internal state and intention [22], and (3) has been strongly implicated in the regulation of social hierarchy behaviors [6]. To investigate neuronal morphology changes in ELS mice, we performed peripheral injection of adeno-associated viral particles containing a GFP construct (AAV9.hSyn.GFP) via the tail vein to achieve a Golgi-like labeling of neurons in the whole mouse brain (see "Materials and methods" section and [17]). We then performed a reconstruction of neurons using confocal microscopy and assessed neuronal arborization and complexity via Sholl analysis.…”