Convergence of hippocampal pathophysiology in <i>Syngap^+/- </i>and <i>Fmr1</i>^<i>-/y</i>mice

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[superscript +/−] and Fmr1[superscript −/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[superscript +/−] hippocampal slices. Super-resolution microscopy reveals that Syngap[superscript +/−] and Fmr1[superscript −/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

Critical Period Plasticity Is Disrupted in the Barrel Cortex of Fmr1 Knockout Mice

SummaryAlterations in sensory processing constitute prominent symptoms of fragile X syndrome; however, little is known about how disrupted synaptic and circuit development in sensory cortex contributes to these deficits. To investigate how the loss of fragile X mental retardation protein (FMRP) impacts the development of cortical synapses, we examined excitatory thalamocortical synapses in somatosensory cortex during the perinatal critical period in Fmr1 knockout mice. FMRP ablation resulted in dysregulation of glutamatergic signaling maturation. The fraction of silent synapses persisting to later developmental times was increased; there was a temporal delay in the window for synaptic plasticity, while other forms of developmental plasticity were not altered in Fmr1 knockout mice. Our results indicate that FMRP is required for the normal developmental progression of synaptic maturation, and loss of this important RNA binding protein impacts the timing of the critical period for layer IV synaptic plasticity

Fragile X syndrome: from targets to treatment

Fragile X Syndrome (FXS) is one of the most prevalent and well-studied monogenetic causes of intellectual disability and autism and, although rare, its high penetrance makes it a desirable model for the study of neurodevelopmental disorders more generally. Indeed recent studies suggest that there is functional convergence of a number of genes that are implicated in intellectual disability and autism indicating that an understanding of the cellular and biochemical dysfunction that occurs in monogenic forms of these disorders are likely to reveal common targets for therapeutic intervention. Fundamental research into FXS has provided a wealth of information about how the loss of function of the fragile X mental retardation protein results in biochemical, anatomical and physiological dysfunction leading to the discovery of interventions that correct many of the core pathological phenotypes associated with animal models of FXS. Most promisingly such strategies have led to development of drugs that are now in clinical trials. This review highlights how progress in understanding disorders such as FXS has led to a new era in which targeted molecular treatment towards neurodevelopmental disorders is becoming a reality

Altered maturation of the primary somatosensory cortex in a mouse model of fragile X syndrome

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and results from the loss of the fragile X mental retardation protein (FMRP). Many fragile X-related cognitive and behavioral features emerge during childhood and are associated with abnormal synaptic and cellular organization of the cerebral cortex. Identifying the roles of FMRP in cortical development will provide a basis for understanding the pathogenesis of the syndrome. However, how the loss of FMRP influences the developmental trajectory of cortical maturation remains unclear. We took advantage of the stereotyped and well-characterized development of the murine primary somatosensory cortex to examine cortical maturation during a time-window that corresponds to late embryonic and early postnatal development in the human. In the Fmr1 knockout mouse, we find a delay in somatosensory map formation, alterations in the morphology profile of dendrites and spines of layer 4 neurons and a decrease in the synaptic levels of proteins involved in glutamate receptor signaling at times corresponding to the highest levels of FMRP expression. In contrast, cortical arealization, synaptic density in layer 4 and early postnatal regulation of mRNAs encoding synaptic proteins are not altered in Fmr1 knockout mice. The specificity of the developmental delay in Fmr1 knockout mice indicates that the loss of FMRP does not result in a general stalling of cerebral cortex maturation. Instead, our results suggest that inaccurate timing of developmental processes caused by the loss of FMRP may lead to alterations in neural circuitry that underlie behavioral and cognitive dysfunctions associated with FXS.status: publishe