Convergence of Hippocampal Pathophysiology inSyngap^+/−andFmr1^−/yMice

Abstract

Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene. Syngap ϩ/Ϫ and Fmr1 Ϫ/y mice show increases in basal protein synthesis and metabotropic glutamate receptor (mGluR)-dependent long-term depression that, unlike in their wild-type controls, is independent of new protein synthesis. Basal levels of phosphorylated ERK1/2 are also elevated in Syngap ϩ/Ϫ hippocampal slices. Super-resolution microscopy reveals that Syngap ϩ/Ϫ and Fmr1 Ϫ/y mice show nanoscale alterations in dendritic spine morphology that predict an increase in biochemical compartmentalization. Finally, increased basal protein synthesis is rescued by negative regulators of the mGlu subtype 5 receptor and the Ras-ERK1/2 pathway, indicating that therapeutic interventions for fragile X syndrome may benefit patients with SYNGAP1 haploinsufficiency.

Autism spectrum disorder: neuropathology and animal models

“…Maturation and size of spines in the hippocampal dentate gyrus of Syngap1 heterozygous mice follow a similar trend to that observed in the somatosensory cortex, although dendritic complexity is not affected in this cortical area [72]. In the hippocampal CA1 of adult mice, the density of mushroom spines, but not those of thin or stubby spines, is increased in Syngap1 +/− mice compared to WT mice [51], although another study using young adult mice reported no change in spine densities or size [22]. Studies using in vitro systems and KO mice have shown that SynGAP expression is inversely correlated to the levels of AMPA receptors, but not NMDA receptors, at the synapse [306].…”

LTD-like molecular pathways in developmental synaptic pruning

“…Similarly, hippocampal mGluR-LTD is enhanced in mice with a deletion for the eIF4E–binding protein 2 gene ( Eif4ebp2 ), which encodes 4E-BP2, a suppressor of mRNA translation initiation 123 . Hippocampal mGluR-LTD is furthermore enhanced in Syngap +/− mice 124 . In these mice, extracellular signal-related kinases 1 and 2 (ERK1/2) signaling is enhanced, which may increase eIF4E cap-dependent translation (for review, see ref.…”

β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X

“…This work suggests that targeting mGlu 5 or its downstream effectors may be a fruitful approach for improving the course of FX and other genetic syndromes with shared pathophysiology (Aguilar-Valles et al, 2015; Auerbach et al, 2011; Barnes et al, 2015; Bozdagi et al, 2010; Tian et al, 2015; Wenger et al, 2016). Indeed, mGlu 5 -based therapies have been immensely successful at correcting FX in animal models (Bhakar et al, 2012).…”