Impaired Critical Period Plasticity in Primary Auditory Cortex of Fragile X Model Mice

“Though other MMPs are increased as well, including MMP-2, MMP-3 and TIMP-2 in adults, MMP-9 has the most prominent and consistent increase in protein levels across ages (Konopka et al., 2013).”

“Some of these deficits may arise due to abnormal critical period plasticity during development (Contractor et al., 2015; Kim et al., 2013).”

“In the auditory cortex, Fmr1 KO mice show abnormal critical period plasticity in response to developmental tone exposure (Kim et al., 2013), which effectively reduces activity- or experienceevoked responses of neuronal networks.”

“Although initial formation of auditory cortex is normal in Fmr1 KO mice, mutants fail to undergo experience-dependent reorganization, suggesting an altered auditory critical period that is mGluR-dependent, as MPEP suppressed the sound-induced reorganization phenotype (Kim et al., 2013a).”

“Hypersensitivity to auditory stimuli in humans with FXS and mice lacking FMRP suggests that development and plasticity in the auditory system may also be affected by the loss of FMRP (Chen and Toth, 2001; Kim et al, 2013a).”

“…and plasticity have been reported in the brainstem (Chen and Toth 2001; Strumbos et al. 2010; Wang et al. 2014; Rotschafer et al. 2015) and auditory cortex (Kim et al. 2013; Rotschafer and Razak 2013; Lovelace et al. 2016; Sinclair et al. 2017; Lovelace et al. 2018) of global Fmr1 KO mice.”

“Transient changes that occur during critical developmental plasticity windows (Dölen et al., 2007; Kim et al., 2013) can induce compensatory mechanisms that can be abnormally stabilized into adulthood.”

“Contribution of social isolation to behavioral dysfunction such as anxiety- or depressive-like behaviors, is thought to be related to modulations to the underlying neurological function of the prefrontal cortex in rodents (Koike et al., 2009; Browne et al., 2016; Liu et al., 2016).”

“CELLULAR NEUROSCIENCE REVIEW ARTICLE published: 25 August 2014 doi: 10.3389/fncel.2014.00245 The contribution of inhibitory interneurons to circuit dysfunction in Fragile X Syndrome”

“Previous studies have shown over-activation and enhanced phosphorylation of Akt/mTOR in the cortex of Fmr1 KO mice (Lovelace et al., 2019) may underlie abnormalities in synaptic functions and hyperexcitability (Klann & Dever, 2004; Sharma et al., 2010).”

“Increased neuronal excitability is detected in a variety of brain regions in Fmr1 /y mice, including the auditory cortex and the lateral superior olive (Kim et al., 2013; Rotschafer and Razak, 2014; Garcia-Pino et al., 2017), as well as the barrel and prefrontal cortex (Zhang et al.”

“These deficits usually arise during the critical period, when sensory cortical circuits are formed, as a consequence of defective synaptic plasticity (Harlow et al., 2010; Kim et al., 2013).”

“…plasticity and mapping of frequency representation during their respective critical periods are impaired in the Fmr1 KO mouse but can be restored by reduction of metabotropic glutamate receptor subunit 5 (mGluR5) expression or pharmacological blockade (Dolen et al., 2007; Kim et al., 2013).”

“Perturbation of auditory experience during this window using tone exposure leads to tonotopic plasticity in the WT mouse, but such critical period plasticity is disrupted in Fmr1 KO mice (66), possibly due to impaired stability of long-term potentiation (67).”

“present for 12 h per day from P9 to P35 (see Materials and Methods), covering previously reported critical periods for auditory cortical plasticity (Zhang et al. 2002; Chang and Merzenich 2003; de Villers-Sidani et al. 2007; Barkat et al. 2011; Kim et al. 2013; Polley et al. 2013).”

“…e.g. congenital cataract, or deaf should receive adequate medical treatment before respectively 6 weeks or 2 years of age to prevent impaired visual acuity (Fledelius, Goldschmidt et al. 2014) or altered auditory perception and language accuracy in adult life (Svirsky, Teoh et al. 2004, Kral 2013).”

“VAF is connected to the insula which is involved in emotion, multisensory integration, and representation of vocal communication sounds (Kimura et al., 2010, 2007; Remedios et al., 2009; Rodgers et al., 2008).”

“Interestingly, in Fmr1 KO mice a previous sound exposure increased the response latency for waves III and IV; a similar exposure decreased latency in control animals (Kim et al., 2013).”

“Mouse models of autism also show impaired auditory cortical development, particularly during the critical period (CP) for tonotopic plasticity (Engineer et al., 2014; Rotschafer and Razak, 2013; Kim et al., 2013).”

“While our negative results on spatial representational expansion in the thalamorecipient layer of cortex are based on a lower spatial sampling density than that used in other mouse studies (Guo et al., 2012; Kim et al., 2013), we note that the same methods were sufficient to reveal map expansion in a developmental sou…”

“Black line and surrounding gray shading in the background indicates mean SEM of the firing rate for evoked (a) or spontaneous (b) conditions in naive FVB mice (n 6, reanalysis of a previously published dataset; Kim et al., 2013).”

“…2014) and the associated auditory deficits such as hyperexcitability, altered frequency tuning, and impaired neural plasticity in auditory neurons (Kim et al., 2013; Rotschafer and Razak, 2013, 2014; Rotschafer et al., 2015; Garcia-Pino et al., 2017), we propose that dysfunctional mGluR…”

“For the normal exposure (NE) group, mice were raised in an accredited vivarium from birth to the day of experiment (background ~65–70 dB SPL; BK Precision, model 732A).”

“Severe auditory cortex deficits have also been observed in the rodent Fmr1 knockout model of fragile X syndrome, the rodent valproic acid model of autism, and the rat Mecp2 knockout model of Rett syndrome [Gandal et al., 2010; Liao et al., 2012; Kim et al., 2013; Engineer et al., 2014a, 2014c, 2015a; Anomal et al., 20…”

“Cortical sound representations, including frequency map, tuning bandwidth, and response thresholds, develop normally in Fmr1 KO mice [12].”

“, 2004), and loss of FMRP impairs critical period plasticity in the visual, auditory, and somatosensory systems (Dölen et al., 2007; Harlow et al., 2010; Kim et al., 2013), possibly by affecting long-term potentiation (Yang et al.”

“…period for responses to simple tones and maturation of tonotopic maps and inhibitory circuits in the auditory cortex (Carrasco et al., 2013; Kim et al., 2013; Oswald and Reyes, 2011) Finally, due to size limitations, it is not possible yet to implant the MEA in skulls younger than P18, and…”

“Additionally, the p14-21 age corresponds to the critical period for responses to tones and maturation of tonotopic maps in the auditory cortex [60, 61].”

“For example, auditory cortical neurons exhibit abnormal auditory responses and impaired neural plasticity (Kim et al., 2013).”

“…depression (Huber et al., 2002; Bear et al., 2004), synaptic plasticity (Larson et al., 2005; Desai et al., 2006; Meredith et al., 2007; Kim et al., 2013), homeostatic plasticity (Soden & Chen, 2010), short-term synaptic plasticity (Deng et al., 2011, 2013), axonal development (Antar…”

“Additionally, the p14-21 age corresponds to the critical period for responses to simple tones and maturation of tonotopic maps in the auditory cortex [71, 72].”

“Animal models of ASD have provided insight into impaired auditory processing, for example concerning cortical plasticity (Kim et al. 2013; Yang et al. 2014), auditory-related learning (Reinhard et al. 2019; Lee et al. 2022), and pitch discrimination (Rendall et al. 2019).”

“This localization is consistent with FMRP as a component of RNA granules in neuronal extensions for distal protein translation (Lai et al., 2020).”

“…interaction signal:Milinkeviciute et al., 2021), this findingopens anewdirection forunderstandingauditory tonotopic development and the emergence of tonotopic alterations in animal models of FXS (Kim et al., 2013; Strumbos et al., 2010) and autism (Anomal et al., 2015; Engineer et al., 2014).”

“Using EEG, Fmr1 KO animals were found to show altered responses at the level of the auditory brainstem response; however, these results were quite inconsistent between studies (El-Hassar et al., 2019; Kim et al., 2013; Rotschafer et al., 2015).”

“This is in contrast with other reports that tone exposure-induced plasticity in the tonotopic organization was diminished in the auditory cortex (Kim et al., 2013) and visual deprivation-induced downregulation of synaptic inhibition was absent in the visual cortex of Fmr1 KO mice (Zhong et al.”

“2001; Chang and Merzenich, 2003), manifested by narrowly tuned spiking receptive fields of individual neurons and a refined tonotopic map across A1 (Zhang et al., 2001; Mrsic-Flogel et al., 2003; Bonham et al., 2004; Kim et al., 2013).”

“Given that the Fmr1 KO mouse also shows auditory critical period plasticity deficits (Kim et al., 2013), the adult mouse recordings may reflect deficits and homeostatic compensatory mechanisms accrued over development (Antoine et al., 2019; Bülow et al., 2019).”

“While the direct cause of altered topographic organization and FRA shapes in FMR1 KO remain unclear at this point, they are probably caused by altered critical period plasticity during development, as observed in the AC (Kim et al., 2013) as well as the barrel cortex (Harlow et al., 2010).”

“…of FXS genotype, but that additionally FXS animals are likely to have alterations in peak amplitude or latency of ABRs and impaired high frequency hearing compared to wildtype consistent with work in other FXS mouse strains (Kim et al., 2013; Rotschafer et al., 2015; El-Hassar et al., 2019).”