Sensory Processing Phenotypes in Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is a neurodevelopmental disorder that causes intellectual disability. It is a leading known genetic cause of autism. In addition to cognitive, social, and communication deficits, humans with FXS demonstrate abnormal sensory processing including sensory hypersensitivity. Sensory hypersensitivity commonly manifests as auditory, tactile, or visual defensiveness or avoidance. Clinical, behavioral, and electrophysiological studies consistently show auditory hypersensitivity, impaired habituation to repeated sounds, and reduced auditory attention in humans with FXS. Children with FXS also exhibit significant visuospatial impairments. Studies in infants and toddlers with FXS have documented impairments in processing texture-defined motion stimuli, temporal flicker, perceiving ordinal numerical sequence, and the ability to maintain the identity of dynamic object information during occlusion. Consistent with the observations in humans with FXS, fragile X mental retardation 1 ( Fmr1) gene knockout (KO) rodent models of FXS also show seizures, abnormal visual-evoked responses, auditory hypersensitivity, and abnormal processing at multiple levels of the auditory system, including altered acoustic startle responses. Among other sensory symptoms, individuals with FXS exhibit tactile defensiveness. Fmr1 KO mice also show impaired encoding of tactile stimulation frequency and larger size of receptive fields in the somatosensory cortex. Since sensory deficits are relatively more tractable from circuit mechanisms and developmental perspectives than more complex social behaviors, the focus of this review is on clinical, functional, and structural studies that outline the auditory, visual, and somatosensory processing deficits in FXS. The similarities in sensory phenotypes between humans with FXS and animal models suggest a likely conservation of basic sensory processing circuits across species and may provide a translational platform to not just develop biomarkers but also to understand underlying mechanisms. We argue that preclinical studies in animal models of FXS can facilitate the ongoing search for new therapeutic approaches in FXS by understanding mechanisms of basic sensory processing circuits and behaviors that are conserved across species.

Keywords: autism spectrum disorders; fragile X syndrome; neurodevelopmental disorders; sensory hypersensitivity.

Figure 1.

Mechanisms of sensory phenotypes associated with FXS. Fragile X syndrome is associated with an expansion of CGG repeats in 5′ untranslated area of the fragile X mental retardation 1 (Fmr1) gene, which leads to silencing Fmr1 gene and a partial or full loss of the fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that regulates translation of mRNAs at synapses, some of which encode proteins involved in protein synthesis and synaptic plasticity. FMRP is known to regulate protein translation through eukaryotic translation elongation factor 1/2 (eEF1/2), argonaute proteins (Ago1/2), eukaryotic translation initiation factor 4 E/G (eIF4E/G), and Dicer. FMRP may also directly regulate phosphatidylinositide-3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), and extracellular signal-regulated kinase (ERK) signaling. Lack of FMRP also leads to enhanced metabotropic glutamate receptor 5 (mGluR5)-mediated long-term depression (LTD), reduced voltage and Ca²⁺ activated K⁺ (BK) channel activity, and increased matrix metalloproteinase-9 (MMP-9) activity, which affect cellular responses resulting in reduced inhibition, impaired development of parvalbumin (PV) interneurons and perineuronal nets (PNN), increased UP states, and abnormal dendritic spine development. These molecular and cellular alterations can contribute to system-level changes, such as impaired development of neural circuits, enhanced resting gamma, and altered excitatory/inhibitory (E/I) balance, which may underlie sensory hypersensitivity and altered behaviors observed in FXS.

Figure 2.

Auditory, visual, and somatosensory processing phenotypes observed in FXS. MMP-9 = matrix metalloproteinase-9; LTD = long-term depression; LTP = long-term potentiation; CPP = critical period plasticity; mGluR5 = metabotropic glutamate receptor 5; E/I = excitatory/inhibitory; PV = parvalbumin interneurons; GABA = gamma-aminobutyric acid; NMDAR = N-methyl-D-aspartate receptor; AMPAR = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.