Research ReportAltered auditory processing in a mouse model of fragile X syndrome
Highlights
► This study examined auditory cortical processing in a mouse model of Fragile X Syndrome. ► Neurons of the auditory cortex of Fmr1 KO mice were hyper-responsive to tones. ► Variability in response latency, broader frequency tuning and altered spectrotemporal processing were also seen. ► These data may serve to explain auditory deficits in humans with Fragile X Syndrome.
Introduction
Fragile X Syndrome (FXS) is a genetic disorder that affects 1 in every 4000 males and 1 in every 8000 females (Hagerman, 2008). FXS results from elongated CGG trinucleotide repeats in the promoter region of the FMR1 gene which become hypermethylated, leading to inactivation of the FMR1 gene and a failure to produce fragile X mental retardation protein (FMRP) (O'Donnell and Warren, 2002). FMRP acts to inhibit the translation of several synaptic mRNAs, and loss of FMRP typically results in an over-production of associated synaptic proteins (Bassell and Warren, 2008). The symptoms of FXS include altered social interactions, hyperactivity, hypersensitivity to sensory stimuli, repetitive behavior, abnormal dendritic spine formation, intellectual disability, language deficits and seizures (Largo and Schinzel, 1985, Hanson et al., 1986, Roberts et al., 2001, Roberts et al., 2007, Fidler et al., 2007, Barnes et al., 2009). FXS is a known genetic cause of autism spectrum disorders (Hagerman, 2008).
FXS patients also display an array of auditory cortex structural and functional abnormalities. There is a reduction in size of the superior temporal gyrus in FXS (Reiss et al., 1994) and a temporal lobe-specific white matter enlargement (Hazlett et al., 2012). Brain activity of FXS patients is diffuse due to activation of more areas in the brain than typically seen in controls when presented with tones (Hall et al., 2011). Electroencephalogram (EEG) studies have demonstrated that FXS patients have enlarged N1 and N2 components when presented with deviant tone stimuli (Castren et al., 2003, Van der Molen et al., 2012a, Van der Molen et al., 2012b), and show unusually slow background rhythm (Wisniewski et al., 1991). N1 is typically associated with activity within the superior temporal gyrus (Scherg and von Cramon, 1986, O'Connor, 2012). Using magnetoencephalography (MEG), Rojas and colleagues showed that the N100 component was enhanced during an auditory oddball task (Rojas et al., 2001). The nature of neuronal deficits in the auditory system that may lead to altered EEG and MEG signals remains unclear.
The goal of the present study was to determine auditory response selectivity at the level of individual neurons in the primary auditory cortex (A1) and the anterior auditory field (AAF) of the Fmr1 knock-out (KO) mouse and compare responses with wild-type (WT) controls. Fmr1 KO mice display several symptoms associated with FXS, and is the commonly used mouse model for FXS. As in humans with FXS, Fmr1 KO mice display abnormal dendritic spine maturation in cortex and hippocampus (Galvez et al., 2003, McKinney et al., 2005, Grossman et al., 2006, Grossman et al., 2010, Cruz-Martin et al., 2010, Pan et al., 2010). There is also evidence that Fmr1 KO mice show social deficits when interacting with other mice, and engage in repetitive behaviors (Mineur et al., 2002, Spencer et al., 2005, Crawley, 2007) and show abnormal social vocalizations (Rotschafer et al., 2012). In the auditory brainstem, FMRP contributes to maintenance of tonotopic gradients in potassium ion channels and KO mice show deficits in experience-dependent plasticity (Strumbos et al., 2010). Fmr1 KO mice also show audiogenic seizures and hypersensitivity to auditory stimuli (Musumeci et al., 2000, Chen and Toth, 2001, Errijgers et al., 2008) as seen in human FXS patients (Hagerman et al., 1986, Hagerman et al., 1991, Miller et al., 1999, Frankland et al., 2004, Hessl et al., 2009, Yuhas et al., 2011). This suggests abnormal responses in the auditory system of the Fmr1 KO mice, but the neural correlates of such deficits have not been previously investigated.
In vitro studies of the Fmr1 KO mice somatosensory cortex have shown abnormalities in the balance between inhibition and excitation in cortical circuits (Gibson et al., 2008, Hays et al., 2011, Paluszkiewicz et al., 2011). Such an imbalance has been postulated as a general mechanism underlying symptoms in several neurodevelopmental disorders (Rubenstein and Merzenich, 2003). It is not known if the auditory cortex in Fmr1 KO mice shows similar changes, but the auditory processing deficits seen in both FXS patients and the Fmr1 KO mice formed the motivation to examine in vivo response selectivity in the auditory cortex. We compared four response properties from single unit recordings across the WT and KO mice: frequency tuning, response magnitude to tones, variability in response latencies and response selectivity for frequency modulated (FM) sweep direction and rate. These properties allow an evaluation of spectral, temporal and spectrotemporal processing in the cortex. We found that Fmr1 KO mouse neurons had significantly broader frequency tuning curves, more jitter in the first spike latency, stronger excitatory response to tones and altered selectivity for FM sweep. However, there was no difference in FM sweep direction selectivity. The changes in auditory response selectivity may explain observed changes in auditory processing in FXS patients and altered sound-driven behaviors in the Fmr1 KO mice.
Section snippets
Results
The main goal of this study was to compare responses of neurons in primary auditory cortex (A1) and anterior auditory field (AAF) to tones and FM sweeps between the Fmr1 knockout (KO) mice and wild-type controls (WT).
Discussion
The goal of this study was to compare cortical responses to tones and FM sweeps between Fmr1 KO mice and WT controls. Compared to neurons from WT mice, neurons in KO mice showed broader frequency tuning, larger response magnitude and more variability of first spike latency when tested with tones. There was no difference in minimum thresholds and in the first spike latency between the groups. In response to FM sweeps, KO neurons were less selective for sweep rates but did not show differences in
Mice
Fmr1 KO mice are available on both FVB and C57bl/6 background strains (Bernardet and Crusio, 2006). The latter strain is subject to accelerated hearing loss and observed results in this study may be confounded by peripheral changes (Spongr et al., 1997). FVB mice do not show early onset hearing loss and hearing thresholds are low up to at least 7 months of age (Zheng et al., 1999). Therefore, we chose the FVB strain in this study. All mice used here were between 1 and 4 months old. FVB.129P2-
Acknowledgments
This work was supported by the FRAXA Research Foundation. We thank members of the Razak lab for useful discussions on the data and the manuscript. We also thank Dr. Iryna Ethell for providing mice for experiments and discussions of the data.
References (81)
- et al.
Mouse auditory cortex differs from visual and somatosensory cortices in the laminar distribution of cytochrome oxidase and acetylcholinesterase
Brain Res.
(2009) - et al.
Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function
Neuron
(2008) - et al.
Fragile X mice develop sensory hyperreactivity to auditory stimuli
Neuroscience
(2001) - et al.
Decreased expression of the GABAA receptor in fragile X syndrome
Brain Res.
(2006) - et al.
Expression of the GABAergic system in animal models for fragile X syndrome and fragile X associated tremor/ataxia syndrome (FXTAS)
Brain Res.
(2009) - et al.
Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice
Neurobiol. Dis.
(2008) - et al.
Somatosensory cortical barrel dendritic abnormalities in a mouse model of the fragile X mental retardation syndrome
Brain Res.
(2003) - et al.
Hippocampal pyramidal cells in adult Fmr1 knockout mice exhibit an immature-appearing profile of dendritic spines
Brain Res.
(2006) - et al.
Developmental characteristics of dendritic spines in the dentate gyrus of Fmr1 knockout mice
Brain Res.
(2010) - et al.
Trajectories of early brain volume development in fragile X syndrome and autism
J. Am. Acad. Child Adolescent Psychiatry
(2012)
AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome
Neurobiol. Dis.
Audiogenic seizure susceptibility is reduced in fragile X knockout mice after introduction of FMR1 transgenes
Exp. Neurol.
The mismatch negativity (MMN) in basic research of central auditory processing: a review
Clin. Neurophysiol.
Alterations in the auditory startle response in Fmr1 targeted mutant mouse models of fragile X syndrome
Brain Res.
Auditory processing in autism spectrum disorder: a review
Neurosci. Biobehav. Rev.
Spectral integration in the inferior colliculus of the CBA/CaJ mouse
Neuroscience
Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of fragile X Syndrome
Brain Res.
Balanced tone-evoked synaptic excitation and inhibition in mouse auditory cortex
Neuroscience
Auditory change detection in fragile X syndrome males: a brain potential study
Clin. Neurophysiol.
Auditory and visual cortical activity during selective attention in fragile X syndrome: a cascade of processing deficiencies
Clin. Neurophysiol.
Gamma-aminobutyric acid circuits shape response properties of auditory cortex neurons
Brain Res.
Lateral sharpening of cortical frequency tuning by approximately balanced inhibition
Neuron
Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses
Hear. Res.
Phonological accuracy and intelligibility in connected speech of boys with fragile X syndrome or Down syndrome
J. Speech Lang. Hear. Res.
Fmr1 KO mice as a possible model of autistic features
Sci. World J.
Responses of neurons in chinchilla auditory cortex to frequency-modulated tones
J. Neurophysiol.
Augmentation of auditory N1 in children with fragile X syndrome
Brain Topogr.
Depth-dependent temporal response properties in core auditory cortex
J. Neurosci.
Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits
Proc. Natl. Acad. Sci. U.S.A.
Auditory evoked potentials from the cortex: audiology applications
Curr. Opin. Otolaryngol. Head Neck Surg.
Mouse behavioral assays relevant to the symptoms of autism
Brain Pathol.
Delayed stabilization of dendritic spines in fragile X mice
J. Neurosci.
Effect of genetic background on acoustic startle response in fragile X knockout mice
Genet. Res. (Camb.)
Language phenotypes and intervention planning: bridging research and practice
Ment. Retard. Dev. Disabil. Res. Rev.
Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice
Mol. Psychiatry
Role of GABA in shaping frequency tuning and creating FM sweep selectivity in the inferior colliculus
J. Neurophysiol.
Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome
J. Neurophysiol.
It's about time: how input timing is used and not used to create emergent properties in the auditory system
J. Neurosci.
Functional organization of squirrel monkey primary auditory cortex: responses to frequency-modulation sweeps
J. Neurophysiol.
The fragile X prevalence paradox
J. Med. Genet.
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