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• W2967355849 abstract "•Distinct pathophysiologies cause peripheral sensory neuron dysfunction in ASD models•Peripheral somatosensory neuron dysfunction alters brain development and behavior•A peripherally restricted GABAAR agonist, isoguvacine, reduces tactile sensitivity•Chronic isoguvacine treatment improves a subset of ASD-related phenotypes in mice Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory over-reactivity and ASDs are lacking. We found distinct somatosensory neuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABAA receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of Mecp2 and Shank3 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors. Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory over-reactivity and ASDs are lacking. We found distinct somatosensory neuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABAA receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of Mecp2 and Shank3 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors. Autism spectrum disorders (ASDs) are a heterogeneous group of complex neurodevelopmental disorders characterized by impairments in social communication and interactions and restricted and repetitive behaviors. Although rates of ASD diagnosis are increasing, with approximately 1 in 59 people in the United States reported to be living with ASD, there are no Food and Drug Administration (FDA)-approved treatments for core ASD symptoms (Baio et al., 2018Baio J. Wiggins L. Christensen D.L. Maenner M.J. Daniels J. Warren Z. Kurzius-Spencer M. Zahorodny W. Robinson Rosenberg C. White T. et al.Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014.MMWR Surveill. Summ. 2018; 67: 1-23Crossref PubMed Scopus (2351) Google Scholar). Furthermore, a majority of adults with ASD (60%) exhibit concerns about current medication options aimed at alleviating co-morbid ASD symptoms due to a lack of efficacy and adverse side effects, including fatigue and sedation (Howes et al., 2018Howes O.D. Rogdaki M. Findon J.L. Wichers R.H. Charman T. King B.H. Loth E. McAlonan G.M. McCracken J.T. Parr J.R. et al.Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology.J. Psychopharmacol. (Oxford). 2018; 32: 3-29Crossref PubMed Scopus (127) Google Scholar). Of note, pharmacological modulators of GABA receptor signaling have gained attention for possible therapeutic utility in patients with ASD. Bumetanide (a selective chloride importer NKCC1 antagonist) and arbaclofen (a GABAB receptor agonist) are being explored as means of restoring GABAergic inhibition and may show promise in recent clinical trials with regards to improving social behaviors in children with ASD, although side effects of fatigue and irritability pose concerns (Erickson et al., 2014Erickson C.A. Veenstra-Vanderweele J.M. Melmed R.D. McCracken J.T. Ginsberg L.D. Sikich L. Scahill L. Cherubini M. Zarevics P. Walton-Bowen K. et al.STX209 (arbaclofen) for autism spectrum disorders: an 8-week open-label study.J. Autism Dev. Disord. 2014; 44: 958-964Crossref PubMed Scopus (90) Google Scholar, Hadjikhani et al., 2018Hadjikhani N. Åsberg Johnels J. Lassalle A. Zürcher N.R. Hippolyte L. Gillberg C. Lemonnier E. Ben-Ari Y. Bumetanide for autism: more eye contact, less amygdala activation.Sci. Rep. 2018; 8: 3602Crossref PubMed Scopus (52) Google Scholar, James et al., 2019James B.J. Gales M.A. Gales B.J. Bumetanide for Autism Spectrum Disorder in Children: A Review of Randomized Controlled Trials.Ann. Pharmacother. 2019; 53: 537-544Crossref PubMed Scopus (21) Google Scholar, Lemonnier et al., 2017Lemonnier E. Villeneuve N. Sonie S. Serret S. Rosier A. Roue M. Brosset P. Viellard M. Bernoux D. Rondeau S. et al.Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders.Transl. Psychiatry. 2017; 7: e1056Crossref PubMed Scopus (119) Google Scholar, Veenstra-VanderWeele et al., 2017Veenstra-VanderWeele J. Cook E.H. King B.H. Zarevics P. Cherubini M. Walton-Bowen K. Bear M.F. Wang P.P. Carpenter R.L. Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial.Neuropsychopharmacology. 2017; 42: 1390-1398Crossref PubMed Scopus (89) Google Scholar). New therapeutic strategies to treat symptoms observed in ASD patients and reduce off-target effects are clearly needed. A major hurdle in developing effective treatments for ASD patients is that symptoms and severity are heterogeneous across individuals. In addition, identifying neurobiological underpinnings of behavioral and cognitive abnormalities in ASD, which are needed for rational drug design, has been challenging. Mounting evidence indicates that sensory processing impairments are a key feature of ASD, and aberrant sensory reactivity is now recognized as a core diagnostic symptom (DSM-V, 2013DSM-VDiagnostic and statistical manual of mental disorders: DSM-5.Fifth Edition. American Psychiatric Publishing, 2013Google Scholar). Furthermore, regression modeling indicates that sensory over-responsivity is strongly correlated with anxiety and gastrointestinal dysfunction, which are frequently co-morbid in people with ASD (Mazurek et al., 2013Mazurek M.O. Vasa R.A. Kalb L.G. Kanne S.M. Rosenberg D. Keefer A. Murray D.S. Freedman B. Lowery L.A. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders.J. Abnorm. Child Psychol. 2013; 41: 165-176Crossref PubMed Scopus (250) Google Scholar). Of particular interest is an emerging body of literature indicating that abnormal responses to touch are highly correlated with—and predictive of—ASD severity. Children with ASD often exhibit greater sensitivity to light touch than children with other developmental disorders (Wiggins et al., 2009Wiggins L.D. Robins D.L. Bakeman R. Adamson L.B. Brief report: sensory abnormalities as distinguishing symptoms of autism spectrum disorders in young children.J. Autism Dev. Disord. 2009; 39: 1087-1091Crossref PubMed Scopus (147) Google Scholar), and touch avoidance during infancy predicts deficits in social development and ASD diagnosis in young children (Mammen et al., 2015Mammen M.A. Moore G.A. Scaramella L.V. Reiss D. Ganiban J.M. Shaw D.S. Leve L.D. Neiderhiser J.M. Infant Avoidance during a Tactile Task Predicts Autism Spectrum Behaviors in Toddlerhood.Infant Ment. Health J. 2015; 36: 575-587Crossref PubMed Scopus (24) Google Scholar). Recent work aimed at identifying the neurobiological basis of abnormal tactile sensitivity in ASD revealed that peripheral mechanosensory neurons, called low-threshold mechanoreceptor neurons (LTMRs), and their connections within the spinal cord (SC), are dysfunctional in Mecp2 and Gabrb3 ASD mouse models due to a loss of GABAA receptor (GABAAR)-dependent presynaptic inhibition (PSI) (Orefice et al., 2016Orefice L.L. Zimmerman A.L. Chirila A.M. Sleboda S.J. Head J.P. Ginty D.D. Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs.Cell. 2016; 166: 299-313Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). Moreover, aberrant tactile reactivity observed in both Mecp2 and Gabrb3 mutant mice contributes to a subset of ASD-associated behavioral phenotypes, including social impairments and anxiety-like behaviors (Orefice et al., 2016Orefice L.L. Zimmerman A.L. Chirila A.M. Sleboda S.J. Head J.P. Ginty D.D. Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs.Cell. 2016; 166: 299-313Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). It remains unclear, however, whether peripheral mechanosensory neuron abnormalities are common across additional pervasive developmental disorders associated with ASD, as well as idiopathic ASD. Furthermore, it is not known whether pharmacological strategies targeting peripheral mechanosensory neurons can be used to treat tactile over-reactivity and other ASD-related behaviors. Here, we report that tactile over-reactivity in different ASD models can result from disparate molecular and pathophysiological mechanisms, aberrant tactile reactivity leads to region-specific abnormal brain development, and a peripherally restricted pharmacological approach to suppress tactile over-reactivity during early postnatal development has the potential to improve some behavioral abnormalities associated with ASD. We previously found that Mecp2 and Gabrb3 function in peripheral somatosensory neurons for normal tactile behaviors (Orefice et al., 2016Orefice L.L. Zimmerman A.L. Chirila A.M. Sleboda S.J. Head J.P. Ginty D.D. Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs.Cell. 2016; 166: 299-313Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar), however, the extent to which dysfunction of the peripheral nervous system (PNS) neurons contributes to altered somatosensation in other genetic models for ASD is not known. Haploinsufficiency of the gene Shank3 causes Phelan-McDermid syndrome, a neurodevelopmental disorder very often presenting with ASD symptoms (Phelan and McDermid, 2012Phelan K. McDermid H.E. The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome).Mol. Syndromol. 2012; 2: 186-201Crossref PubMed Scopus (300) Google Scholar). Patients with Phelan-McDermid syndrome often exhibit enhanced sensitivity to light touch stimuli and tactile defensiveness and, paradoxically, reduced responsivity to certain painful stimuli (Phelan and McDermid, 2012Phelan K. McDermid H.E. The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome).Mol. Syndromol. 2012; 2: 186-201Crossref PubMed Scopus (300) Google Scholar, Philippe et al., 2008Philippe A. Boddaert N. Vaivre-Douret L. Robel L. Danon-Boileau L. Malan V. de Blois M.C. Heron D. Colleaux L. Golse B. et al.Neurobehavioral profile and brain imaging study of the 22q13.3 deletion syndrome in childhood.Pediatrics. 2008; 122: e376-e382Crossref PubMed Scopus (79) Google Scholar). Mice with a germline loss-of-function mutation in Shank3 (Shank3B+/−) exhibit ASD-like traits (Jaramillo et al., 2017Jaramillo T.C. Speed H.E. Xuan Z. Reimers J.M. Escamilla C.O. Weaver T.P. Liu S. Filonova I. Powell C.M. Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function.Autism Res. 2017; 10: 42-65Crossref PubMed Scopus (63) Google Scholar, Peça et al., 2011Peça J. Feliciano C. Ting J.T. Wang W. Wells M.F. Venkatraman T.N. Lascola C.D. Fu Z. Feng G. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.Nature. 2011; 472: 437-442Crossref PubMed Scopus (982) Google Scholar), including tactile over-reactivity (Orefice et al., 2016Orefice L.L. Zimmerman A.L. Chirila A.M. Sleboda S.J. Head J.P. Ginty D.D. Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs.Cell. 2016; 166: 299-313Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). SHANK3 is a synaptic protein that is expressed in both mouse and human dorsal root ganglion (DRG) neurons (Ray et al., 2018Ray P. Torck A. Quigley L. Wangzhou A. Neiman M. Rao C. Lam T. Kim J.Y. Kim T.H. Zhang M.Q. et al.Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq-based resource for pain and sensory neuroscience research.Pain. 2018; 159: 1325-1345Crossref PubMed Scopus (166) Google Scholar, Usoskin et al., 2015Usoskin D. Furlan A. Islam S. Abdo H. Lönnerberg P. Lou D. Hjerling-Leffler J. Haeggström J. Kharchenko O. Kharchenko P.V. et al.Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing.Nat. Neurosci. 2015; 18: 145-153Crossref PubMed Scopus (1131) Google Scholar), including at the presynaptic terminals of LTMRs that are responsible for transmitting light touch information to the SC dorsal horn (Figure S1A). We therefore asked whether peripheral mechanosensory neuron dysfunction in Shank3 mutant mice underlies abnormal innocuous touch behaviors. To address this, we generated a mouse line harboring a Shank3 floxed (Shank3f) allele (Figures S1B–S1D) to enable selective ablation of Shank3 in cells expressing Cre recombinase. Shank3f mice were crossed with mice expressing Cre recombinase below cervical level 2 (Cdx2Cre; Shank3f/+) (Akyol et al., 2008Akyol A. Hinoi T. Feng Y. Bommer G.T. Glaser T.M. Fearon E.R. Generating somatic mosaicism with a Cre recombinase-microsatellite sequence transgene.Nat. Methods. 2008; 5: 231-233Crossref PubMed Scopus (34) Google Scholar) or all DRG, trigeminal, and sympathetic ganglia neurons (AdvillinCre; Shank3f/+ or f/f) (Hasegawa et al., 2007Hasegawa H. Abbott S. Han B.X. Qi Y. Wang F. Analyzing somatosensory axon projections with the sensory neuron-specific Advillin gene.J. Neurosci. 2007; 27: 14404-14414Crossref PubMed Scopus (107) Google Scholar) (Figure S1A). Of note, Shank3 is expressed at almost undetectable levels in sympathetic neurons (Furlan et al., 2016Furlan A. La Manno G. Lübke M. Häring M. Abdo H. Hochgerner H. Kupari J. Usoskin D. Airaksinen M.S. Oliver G. et al.Visceral motor neuron diversity delineates a cellular basis for nipple- and pilo-erection muscle control.Nat. Neurosci. 2016; 19: 1331-1340Crossref PubMed Scopus (56) Google Scholar). These conditional mutants as well as mice with heterozygous germline Shank3 deletion (Shank3B+/−) and, for comparison, mice with sensory-neuron-specific deletion of Mecp2 (AdvillinCre; Mecp2f/+ or f/y), were subjected to behavioral assays to assess tactile sensitivity and ASD-related behaviors. Consistent with previous findings, Shank3B+/− and AdvillinCre; Mecp2f/+ or f/y mutant mice exhibited hairy skin hypersensitivity, measured by a tactile prepulse inhibition of an acoustic startle response assay (tactile PPI) and responsivity to an air puff stimulus alone delivered to back hairy skin (Figures 1A and 1B ; Table S1) (Orefice et al., 2016Orefice L.L. Zimmerman A.L. Chirila A.M. Sleboda S.J. Head J.P. Ginty D.D. Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs.Cell. 2016; 166: 299-313Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). Shank3B+/− and AdvillinCre; Mecp2f/+ or f/y mutant mice also displayed texture discrimination deficits, assessed using a textured novel object recognition test (“textured NORT”) (Figure 1C) (Orefice et al., 2016Orefice L.L. Zimmerman A.L. Chirila A.M. Sleboda S.J. Head J.P. Ginty D.D. Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs.Cell. 2016; 166: 299-313Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). Loss of Shank3 in cells below the neck (Cdx2Cre; Shank3f/+) or in somatosensory neurons (AdvillinCre; Shank3f/+ or f/f) also led to an increase in tactile PPI, increased responsivity to an air puff stimulus, and deficits in texture discrimination (Figures 1A–1C). Cdx2Cre; Shank3f/+ and AdvillinCre; Shank3f/+ or f/f mutant mice were overtly normal, however, and no differences in gross motor behaviors, acoustic PPI, or memory retention were observed among any of the groups (Figures S1E–S1J).Figure 1Shank3 Functions Cell-Autonomously in Peripheral Somatosensory Neurons for Normal Innocuous Touch BehaviorsShow full caption(A) Hairy skin sensitivity was measured using tactile PPI. Percent inhibition of the startle response to a 125 dB noise, when the startle noise is preceded by a light air puff (250 ms ISI). Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05.(B) Response to a light air puff stimulus alone directed to the back hairy skin. Responses are expressed as percent of startle response to a 125 dB noise. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05.(C) Texture discrimination was measured using the textured NORT behavioral assay. A positive value indicates preference for the novel object, compared to the familiar object. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05.(D) Open field (OF) test was used as a general measure of exploration and anxiety-like behavior. Shown are representative activity traces in the OF test for mutant mice and control littermates. OF chamber is 40 cm by 40 cm.(E) Percent time spent in the center of the OF chamber. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05.(F) Percent time spent in the open arms of the EPM. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05.(G) Preference index for the percentage of time spent investigating a novel mouse, compared to a novel object, in the “Sociability” portion of the 3-chamber social interaction test. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05; #p < 0.10.(H) Preference index for the percentage of time spent investigating a novel mouse, compared to a familiar mouse, in the “Social Novelty Preference” portion of the 3-chamber social interaction test. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05; #, p < 0.10.(I) Voltage step protocol used to activate HCN channels and elicit Ih during whole-cell voltage clamp recordings.(J and K) Representative electrophysiological traces showing Ih during a hyperpolarizing voltage step protocol in large diameter DRG neurons cultured from control and Shank3B+/− mutant mice, at baseline (J) and with a selective HCN-channel blocker, ZD-7288 (K).(L) Quantification of Ih density at each voltage step for large diameter neurons cultured from DRGs of control and mutant mice. Two-way ANOVA with post hoc Sidak’s test, (F[1,1,470] = 187.7; p < 0.0001) ∗p < 0.05.(M) Representative traces from large diameter DRG neurons cultured from control and Shank3B+/− mutant mice during whole cell current clamp recordings, in which the minimal amount of current required to elicit an action potential in each neuron (rheobase [Rh]), was determined.(N) Quantification of average Rh in large diameter DRG neurons cultured from control and Shank3B+/− mutant mice. Student’s unpaired t test, ∗p < 0.005.Error bars indicate standard error of the mean. See also Figures S1 and S2 and Tables S1, S2, and S7.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) Hairy skin sensitivity was measured using tactile PPI. Percent inhibition of the startle response to a 125 dB noise, when the startle noise is preceded by a light air puff (250 ms ISI). Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05. (B) Response to a light air puff stimulus alone directed to the back hairy skin. Responses are expressed as percent of startle response to a 125 dB noise. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05. (C) Texture discrimination was measured using the textured NORT behavioral assay. A positive value indicates preference for the novel object, compared to the familiar object. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05. (D) Open field (OF) test was used as a general measure of exploration and anxiety-like behavior. Shown are representative activity traces in the OF test for mutant mice and control littermates. OF chamber is 40 cm by 40 cm. (E) Percent time spent in the center of the OF chamber. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05. (F) Percent time spent in the open arms of the EPM. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05. (G) Preference index for the percentage of time spent investigating a novel mouse, compared to a novel object, in the “Sociability” portion of the 3-chamber social interaction test. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05; #p < 0.10. (H) Preference index for the percentage of time spent investigating a novel mouse, compared to a familiar mouse, in the “Social Novelty Preference” portion of the 3-chamber social interaction test. Student’s unpaired t test or one-way ANOVA with post hoc Tukey’s test, ∗p < 0.05; #, p < 0.10. (I) Voltage step protocol used to activate HCN channels and elicit Ih during whole-cell voltage clamp recordings. (J and K) Representative electrophysiological traces showing Ih during a hyperpolarizing voltage step protocol in large diameter DRG neurons cultured from control and Shank3B+/− mutant mice, at baseline (J) and with a selective HCN-channel blocker, ZD-7288 (K). (L) Quantification of Ih density at each voltage step for large diameter neurons cultured from DRGs of control and mutant mice. Two-way ANOVA with post hoc Sidak’s test, (F[1,1,470] = 187.7; p < 0.0001) ∗p < 0.05. (M) Representative traces from large diameter DRG neurons cultured from control and Shank3B+/− mutant mice during whole cell current clamp recordings, in which the minimal amount of current required to elicit an action potential in each neuron (rheobase [Rh]), was determined. (N) Quantification of average Rh in large diameter DRG neurons cultured from control and Shank3B+/− mutant mice. Student’s unpaired t test, ∗p < 0.005. Error bars indicate standard error of the mean. See also Figures S1 and S2 and Tables S1, S2, and S7. Concomitant with altered reactivity to tactile stimuli, mice in which either Mecp2 or Gabrb3 was ablated in peripheral somatosensory neurons during embryonic development exhibited increased anxiety-like behaviors and abnormal social behaviors in adulthood (Figures 1D–1H and S1K–S1M) (Orefice et al., 2016Orefice L.L. Zimmerman A.L. Chirila A.M. Sleboda S.J. Head J.P. Ginty D.D. Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs.Cell. 2016; 166: 299-313Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). We therefore hypothesized that altered tactile processing due to developmental loss of Shank3 in peripheral sensory neurons may also contribute to anxiety-like behaviors and abnormal social behaviors in adult mice. Consistent with prior findings, Shank3B+/− mice displayed anxiety-like behaviors in the open field test, elevated plus maze (EPM), and lack of habituation to an acoustic startle noise (Peça et al., 2011Peça J. Feliciano C. Ting J.T. Wang W. Wells M.F. Venkatraman T.N. Lascola C.D. Fu Z. Feng G. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.Nature. 2011; 472: 437-442Crossref PubMed Scopus (982) Google Scholar) (Figures 1D–1F and S1K–S1M). Cdx2Cre; Shank3f/+, and AdvillinCre; Shank3f/+ or f/f mutant mice also exhibited anxiety-like behaviors (Figures 1D–1F and S1K–S1M). Abnormal social interactions, neophobia, and over-grooming behaviors are additional features of Shank3B+/− mutant mice (Jaramillo et al., 2017Jaramillo T.C. Speed H.E. Xuan Z. Reimers J.M. Escamilla C.O. Weaver T.P. Liu S. Filonova I. Powell C.M. Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function.Autism Res. 2017; 10: 42-65Crossref PubMed Scopus (63) Google Scholar, Peça et al., 2011Peça J. Feliciano C. Ting J.T. Wang W. Wells M.F. Venkatraman T.N. Lascola C.D. Fu Z. Feng G. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction.Nature. 2011; 472: 437-442Crossref PubMed Scopus (982) Google Scholar). We implemented the three-chamber social interaction test to assess sociability and social novelty recognition preference (“social novelty preference”) in the conditional mutants (Silverman et al., 2010Silverman J.L. Yang M. Lord C. Crawley J.N. Behavioural phenotyping assays for mouse models of autism.Nat. Rev. Neurosci. 2010; 11: 490-502Crossref PubMed Scopus (1010) Google Scholar). Similar to Shank3B+/− mice, the Cdx2Cre; Shank3f/+ and AdvillinCre; Shank3f/+ or f/f mice did not show a preference for a novel mouse in either the sociability or social novelty preference portion of the test, although Cdx2Cre; Shank3f/+ and AdvillinCre; Shank3f/+ mutants did exhibit a trend toward preference in the sociability assay (Figures 1G and 1H; Table S2). Shank3+/− mice exhibited neophobia during a marble burying task, evidenced by a decreased number of marbles buried compared to controls (Jaramillo et al., 2017Jaramillo T.C. Speed H.E. Xuan Z. Reimers J.M. Escamilla C.O. Weaver T.P. Liu S. Filonova I. Powell C.M. Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function.Autism Res. 2017; 10: 42-65Crossref PubMed Scopus (63) Google Scholar) (Figure S1N). A modest decrease in the number of marbles buried was also observed in Cdx2Cre; Shank3f/+ and AdvillinCre; Shank3f/+ or f/f mutant mice (Figure S1N). Finally, while Shank3B+/− mutants display an overgrooming behavior, this phenotype was not observed in either Cdx2Cre; Shank3f/+ or AdvillinCre; Shank3f/f mice (Figure S1O). These findings indicate that a subset of behavioral abnormalities observed in Shank3B+/− mice are also observed in mice lacking one or both Shank3 alleles in peripheral somatosensory neurons. We next asked whether restoration of Shank3 expression selectively in peripheral somatosensory neurons might improve tactile deficits and other ASD-related phenotypes observed in Shank3 germline mutant mice. We employed a Cre-dependent genetic switch (FLEx) knockin mouse, which enables conditional expression of Shank3 from its endogenous genomic locus in the presence of Cre recombinase (Mei et al., 2016Mei Y. Monteiro P. Zhou Y. Kim J.A. Gao X. Fu Z. Feng G. Adult restoration of Shank3 expression rescues selective autistic-like phenotypes.Nature. 2016; 530: 481-484Crossref PubMed Scopus (243) Google Scholar) (Figure S1Q). Selective restoration of Shank3 in cells below the neck (Cdx2Cre; Shank3FX/+) or in somatosensory neurons (AdvillinCre; Shank3FX/+) (Figures S1Q and S1R) normalized hairy skin hypersensitivity, textured discrimination deficits and anxiety-like behaviors observed in Shank3FX/+ mice (Figures 1A–1F and S1L). Furthermore, while Shank3FX/+ mice did not show a preference for a novel mouse in either portion of the 3-chamber social interaction test, both Cdx2Cre; Shank3FX/+ and AdvillinCre; Shank3FX/+ rescue mice exhibited preference for the novel mouse in the sociability assay (Figures 1G and 1H; Table S2). We also observed an intermediate phenotype in the marble burying test: Cdx2Cre; Shank3FX/+ and AdvillinCre; Shank3FX/+ rescue mice buried more marbles than their Shank3FX/+ littermates, but fewer than control littermates (Figure S1N). Conversely, no improvements in memory deficits or overgrooming behaviors were observed in either Cdx2Cre; Shank3FX/+ or AdvillinCre; Shank3FX/+ rescue mice (Figures S1I, S1O, and S1P). Therefore, as observed for Mecp2 and Gabrb3 (Orefice et al., 2016Orefice L.L. Zimmerman A.L. Chirila A.M. Sleboda S.J. Head J.P. Ginty D.D. Peripheral Mechanosensory Neuron Dysfunction Underlies Tactile and Behavioral Deficits in Mouse Models of ASDs.Cell. 2016; 166: 299-313Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar), Shank3 is required cell-autonomously in peripheral somatosensory neurons for normal tactile sensitivity and texture discrimination as well as a subset of ASD-related behaviors. Thus, dysfunction of mechanosensory neurons is a common feature of multiple ASD mouse models, despite disparate molecular properties and functions of ASD-associated genes. Prior work indicated that peripheral somatosensory neurons lacking Mecp2 or Gabrb3 exhibit decreased expression of GABRB3, the obligatory beta subunit of the GABAAR in these neurons (Orefice et al., 2016Orefice L.L. Zimmerman A.L. Chirila A.M. Sleboda S.J. Head J.P. Ginty D.D. Peripheral Mechanosensory Neuron Dysfuncti" @default.
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• W2967355849 creator A5058053110 @default.
• W2967355849 creator A5059633950 @default.
• W2967355849 creator A5064258463 @default.
• W2967355849 date "2019-08-01" @default.
• W2967355849 modified "2023-10-17" @default.
• W2967355849 title "Targeting Peripheral Somatosensory Neurons to Improve Tactile-Related Phenotypes in ASD Models" @default.
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