Negative Allosteric Modulation of the mGluR5 Receptor Reduces Repetitive Behaviors and Rescues Social Deficits in Mouse Models of Autism

In the paper

“To incorporate construct validity for the various genetic mutations identified in small numbers of people with autism (12–21), these mutations have been generated in mice (22, 23).”

What the sources say

• Supported

  The source reports NLGN3 and NLGN4 mutations in two families, each with affected siblings (mutation-screening passage). In the citing sentence, references 12–21 support the identification of mutations in small numbers of people with autism; the separate claim that mutations were generated in mice is attributed to references 22 and 23, not this paper. (LLM, conf=0.93)

  cites [12] Jamain S Quach H Betancur C Råstam M Colineaux C Gillberg IC Soderstrom H Giros B Leboyer M Gillberg C Bourgeron T Paris Autism Research International Sibpair Study, Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism Nat Genet 34 27 29 2003 12669065 PMC1925054 source
• Not checked yetcites [13] Abrahams BS Geschwind DH Advances in autism genetics: On the threshold of a new neurobiology Nat Rev Genet 9 341 355 2008 18414403 PMC2756414 source
• Supported

  The Discussion (p. 7) reports a CNTNAP2 microdeletion in one autistic proband and discusses rare CNTNAP2 variants found in other patients with autism. In the citing sentence, this source supports the identification of genetic variants in a small number of people; the separate citations (22, 23) attach to generating mutations in mice. (LLM, conf=0.88)

  cites [14] Alarcón M Abrahams BS Stone JL Duvall JA Perederiy JV Bomar JM Sebat J Wigler M Martin CL Ledbetter DH Nelson SF Cantor RM Geschwind DH Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene Am J Hum Genet 82 150 159 2008 18179893 PMC2253955 source
• Not checked yetcites [15] Brune CW Korvatska E Allen-Brady K Cook EH Jr Dawson G Devlin B Estes A Hennelly M Hyman SL McMahon WM Munson J Rodier PM Schellenberg GD Stodgell CJ Coon H Heterogeneous association between engrailed-2 and autism in the CPEA network Am J Med Genet B Neuropsychiatr Genet 147B 187 193 2008 17948868 source
• Supported

  The NLGN3/4 section reports rare mutations identified in people with ASD and says the R451C mutation was introduced into mice. It also describes a mouse model with disrupted Nlgn4x, supporting the claim that identified autism-related genetic changes have been modeled in mice. (LLM, conf=0.89)

  cites [16] Buxbaum JD Multiple rare variants in the etiology of autism spectrum disorders Dialogues Clin Neurosci 11 35 43 2009 19432386 PMC3181906 source
• Not checked yetcites [17] Gauthier J Spiegelman D Piton A Lafrenière RG Laurent S St-Onge J Lapointe L Hamdan FF Cossette P Mottron L Fombonne E Joober R Marineau C Drapeau P Rouleau GA Novel de novo SHANK3 mutation in autistic patients Am J Med Genet B Neuropsychiatr Genet 150B 421 424 2009 18615476 source
• Supported

  The paper’s Abstract (page unavailable) reports copy-number variants in people with autism and says the variants may be individually rare. That supports the portion attributed to this source: genetic variants identified in small numbers of people with autism. The mouse-model portion of the sentence is assigned to citations 22 and 23, not this paper. (LLM, conf=0.89)

  cites [18] Glessner JT Wang K Cai G Korvatska O Kim CE Wood S Zhang H Estes A Brune CW Bradfield JP Imielinski M Frackelton EC Reichert J Crawford EL Munson J Sleiman PM Chiavacci R Annaiah K Thomas K Hou C Glaberson W Flory J Otieno F Garris M Soorya L Klei L Piven J Meyer KJ Anagnostou E Sakurai T Game RM Rudd DS Zurawiecki D McDougle CJ Davis LK Miller J Posey DJ Michaels S Kolevzon A Silverman JM Bernier R Levy SE Schultz RT Dawson G Owley T McMahon WM Wassink TH Sweeney JA Nurnberger JI Coon H Sutcliffe JS Minshew NJ Grant SF Bucan M Cook EH Buxbaum JD Devlin B Schellenberg GD Hakonarson H Autism ge source
• Supported

  The Results section (‘Rare genetic variation in candidate 16p11.2 genes’) reports 26 novel autism-specific rare variants identified after initially sequencing approximately 100 unrelated autistic subjects. This supports the human-mutation finding to which this source is cited. The separate statement that mutations were generated in mice is attributed to citations 22 and 23, not to this paper. (LLM, conf=0.90)

  cites [19] Kumar RA Marshall CR Badner JA Babatz TD Mukamel Z Aldinger KA Sudi J Brune CW Goh G Karamohamed S Sutcliffe JS Cook EH Geschwind DH Dobyns WB Scherer SW Christian SL Association and mutation analyses of 16p11.2 autism candidate genes PLoS One 4 e4582 2009 19242545 PMC2644762 source
• Not checked yetcites [20] Berkel S Marshall CR Weiss B Howe J Roeth R Moog U Endris V Roberts W Szatmari P Pinto D Bonin M Riess A Engels H Sprengel R Scherer SW Rappold GA Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation Nat Genet 42 489 491 2010 20473310 source
• Supported

  The GENES INVOLVED IN AUTISM section reports NLGN3 and NLGN4 mutations in brothers with autism and describes an NLGN4 mutation in a family where some affected members were autistic. This supports the human-mutation clause, to which citations 12–21 are attached; the separate claim about generating mutations in mice is assigned to citations 22 and 23. (LLM, conf=0.87)

  cites [21] Miles JH Autism spectrum disorders—A genetics review Genet Med 13 278 294 2011 21358411 source

In the paper

“No evidence of sedation was detected in any strain at any dose during a 30-min test session (Fig. 5 and figs. S4 to S6).”

In the paper

“Further, GRN-529 partially reversed the striking lack of sociability in BTBR mice on some parameters of social approach and reciprocal social interactions.”

In the paper

“GRN-529 reduced repetitive behaviors in three cohorts of BTBR mice at doses that did not induce sedation in control assays of open field locomotion.”

In the paper

“In addition, the same nonsedating doses reduced the spontaneous stereotyped jumping that characterizes a second inbred strain of mice, C58/J.”

In the paper

“In three replications by two laboratories, acute administration of GRN-529 significantly reduced repetitive self-grooming scores in BTBR (Fig. 2, B and D, and fig. S1F) at doses that achieved 50 to 90% receptor occupancy (Fig. 1F).”

In the paper

“Further, during the freely moving, dyadic reciprocal interaction task, BTBR mice treated with vehicle engaged in much longer bouts of self-grooming and repetitive digging than did B6 mice (Fig. 4, E to H).”

In the paper

“A 30- to 60-min timeframe was chosen for occupancy and behavioral experiments because a 2-hour time course of plasma and brain exposure after GRN-529 administration revealed that peak concentrations occurred between 0 and 60 min in B6 mice (Fig. 1E).”

In the paper

“B6 control mice spent more time in the side chamber containing a novel mouse than in the side chamber containing a novel object, meeting the definition of normal sociability in this task, as extensively reported (22, 62, 64, 72–74, 87–89).”

In the paper

“The effects in C58 were not attributable to reduced locomotion or sedation (Fig. 2F and fig. S6).”

In the paper

“GRN-529 and the prototypic mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) reduced the high levels of repetitive self-grooming that characterizes the BTBR strain.”

In the paper

“GRN-529 did not affect the sociability in B6 controls at any dose (Fig. 3, A and C).”

In the paper

“The relationship between GRN-529 brain exposure and mGluR5 occupancy was similar in B6, BTBR, and C58 mouse strains (Fig. 1F).”

In the paper

“GRN-529 did not affect general exploratory locomotion in B6 and BTBR mice during the reciprocal interaction session (fig. S3, G to J).”

In the paper

“BTBR mice spent significantly more time sniffing the novel mouse than the novel object after doses of 0.3, 1.0, and 3.0 mg/kg (Fig. 3B).”

In the paper

“BTBR mice displayed lack of sociability, defined as not spending more time in the side chamber with the novel mouse than in the side chamber with the novel object, as reported (22, 62, 64, 72–74, 87).”

In the paper

“C58 mice displayed high levels of stereotyped vertical jumping (Fig. 2E), consistent with previous findings (67).”

In the paper

“Consistent with previous reports (62, 64, 69, 72, 74), BTBR mice treated with vehicle engaged in much longer bouts of self-grooming than did B6 (Fig. 2 and fig. S1).”

In the paper

“GRN-529 reversed sociability deficits in BTBR at a dose of 3.0 mg/kg, as measured by time in the chamber (Fig. 3D).”

In the paper

“No increases in total distance traveled were observed in C58 mice at any dose of GRN-529 tested (Fig. 2F).”

In the paper

“No evidence of sedation was detected in any strain at any dose during a 30-min test session (Fig. 5 and figs. S4 to S6).”

In the paper

“Treatment with GRN-529 at these doses reversed the social approach deficits in BTBR on two standardized mouse assays for sociability.”

In the paper

“Further, GRN-529 markedly reduced a stereotyped behavior in another inbred strain, vertical jumping in C58.”

In the paper

“We discovered strong reductions in the repetitive self-grooming phenotype in the BTBR mouse model of autism after GRN-529 treatment, replicated in three cohorts of mice at two research sites.”

In the paper

“Using pharmaco-kinetic and ex vivo receptor occupancy studies, we demonstrated brain exposure and target engagement for GRN-529 across the efficacious dose range (0.3 to 3.0 mg/kg) in B6, BTBR, and C58 mice.”

In the paper

“Acute administration of GRN-529 significantly reduced these spontaneous repetitive behaviors within a social context (Fig. 4, F and H).”

In the paper

“No qualitatively unusual behaviors were observed after GRN-529 treatments during any of the grooming, social, or open field test sessions.”

In the paper

“Intensive behavioral therapy is currently the only effective treatment for the three diagnostic symptoms: qualitative impairment in social interaction, deficits in communication, and stereotyped repetitive behaviors with restricted interests (5–10).”

What the sources say

• Not checked yetcites [5] American Psychiatric Association Diagnostic Criteria from DSM-IV American Psychiatric Association Washington, DC 1994
• Not checked yetcites [6] Lord C Risi S Lambrecht L Cook EH Jr Leventhal BL DiLavore PC Pickles A Rutter M The autism diagnostic observation schedule—Generic: A standard measure of social and communication deficits associated with the spectrum of autism J Autism Dev Disord 30 205 223 2000 11055457 source
• Not checked yetcites [7] Krasny L Williams BJ Provencal S Ozonoff S Social skills interventions for the autism spectrum: Essential ingredients and a model curriculum Child Adolesc Psychiatr Clin N Am 12 107 122 2003 12512401 source
• Not checked yetcites [8] Landa RJ Diagnosis of autism spectrum disorders in the first 3 years of life Nat Clin Pract Neurol 4 138 147 2008 18253102 source
• Not checked yetcites [9] Zwaigenbaum L Bryson S Lord C Rogers S Carter A Carver L Chawarska K Constantino J Dawson G Dobkins K Fein D Iverson J Klin A Landa R Messinger D Ozonoff S Sigman M Stone W Tager-Flusberg H Yirmiya N Clinical assessment and management of toddlers with suspected autism spectrum disorder: Insights from studies of high-risk infants Pediatrics 123 1383 1391 2009 19403506 PMC2833286 source
• Not checked yetcites [10] Dawson G Rogers S Munson J Smith M Winter J Greenson J Donaldson A Varley J Randomized, controlled trial of an intervention for toddlers with autism: The Early Start Denver Model Pediatrics 125 e17 e23 2010 19948568 PMC4951085 source

In the paper

“Experimental interventions, working through diverse genetic and pharmacological mechanisms, rescue subsets of behavioral abnormalities in these mouse models (31, 43, 48–52).”

What the sources say

• Not checked yetcites [31] Guy J Gan J Selfridge J Cobb S Bird A Reversal of neurological defects in a mouse model of Rett syndrome Science 315 1143 1147 2007 17289941 PMC7610836 source
• Not checked yetcites [43] Peñagarikano O Abrahams BS Herman EI Winden KD Gdalyahu A Dong H Sonnenblick LI Gruver R Almajano J Bragin A Golshani P Trachtenberg JT Peles E Geschwind DH Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits Cell 147 235 246 2011 21962519 PMC3390029 source
• Not checked yetcites [48] Hayashi ML Rao BS Seo JS Choi HS Dolan BM Choi SY Chattarji S Tonegawa S Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice Proc Natl Acad Sci USA 104 11489 11494 2007 17592139 PMC1899186 source
• Not checked yetcites [49] Ehninger D Han S Shilyansky C Zhou Y Li W Kwiatkowski DJ Ramesh V Silva AJ Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis Nat Med 14 843 848 2008 18568033 PMC2664098 source
• Not checked yetcites [50] Ehninger D Li W Fox K Stryker MP Silva AJ Reversing neurodevelopmental disorders in adults Neuron 60 950 960 2008 19109903 PMC2710296 source
• Not checked yetcites [51] Cobb S Guy J Bird A Reversibility of functional deficits in experimental models of Rett syndrome Biochem Soc Trans 38 498 506 2010 20298210 source
• Not checked yetcites [52] Zhou J Blundell J Ogawa S Kwon CH Zhang W Sinton C Powell CM Parada LF Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice J Neurosci 29 1773 1783 2009 19211884 PMC3904448 source

In the paper

“Discovery of elevated metabotropic glutamate receptor subtype 5 (mGluR5)–mediated signaling and protein synthesis in fragile X knockout mice (53–56) provided the rationale for testing mGluR5 antagonists in ongoing fragile X clinical trials.”

What the sources say

• Not checked yetcites [53] Bear MF Huber KM Warren ST The mGluR theory of fragile X mental retardation Trends Neurosci 27 370 377 2004 15219735 source
• Not checked yetcites [54] Dölen G Osterweil E Rao BS Smith GB Auerbach BD Chattarji S Bear MF Correction of fragile X syndrome in mice Neuron 56 955 962 2007 18093519 PMC2199268 source
• Not checked yetcites [55] Krueger DD Bear MF Toward fulfilling the promise of molecular medicine in fragile X syndrome Annu Rev Med 62 411 429 2011 21090964 PMC3100156 source
• Not checked yetcites [56] Jacquemont S Curie A des Portes V Torrioli MG Berry-Kravis E Hagerman RJ Ramos FJ Cornish K He Y Paulding C Neri G Chen F Hadjikhani N Martinet D Meyer J Beckmann JS Delange K Brun A Bussy G Gasparini F Hilse T Floesser A Branson J Bilbe G Johns D Gomez-Mancilla B Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056 Sci Transl Med 3 64ra1 2011 21209411 source

In the paper

“Behavioral phenotypes with face validity for some of the diagnostic symptoms of autism have been reported in some of these mutant mouse models (24–47).”

What the sources say

• Not checked yetcites 24–47

In the paper

“These inbred strains are genetically homogeneous and commercially available, maximizing their feasibility as translational tools in medications development (71–73).”

What the sources say

• Not checked yetcites [71] Wagner GC Avena N Kita T Nakashima T Fisher H Halladay AK Risperidone reduction of amphetamine-induced self-injurious behavior in mice Neuropharmacology 46 700 708 2004 14996547 source
• Not checked yetcites [72] Silverman JL Tolu SS Barkan CL Crawley JN Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP Neuropsychopharmacology 35 976 989 2010 20032969 PMC2827881 source
• Not checked yetcites [73] Yang M Perry K Weber MD Katz AM Crawley JN Social peers rescue autism-relevant sociability deficits in adolescent mice Autism Res 4 17 27 2011 20928844 PMC3065860 source

In the paper

“A large subset of cases of fragile X meet the diagnostic criteria for autism (57, 58).”

What the sources say

• Not checked yetcites [57] Hatton DD Sideris J Skinner M Mankowski J Bailey DB Jr Roberts J Mirrett P Autistic behavior in children with fragile X syndrome: Prevalence, stability, and the impact of FMRP Am J Med Genet A 140A 1804 1813 2006 16700053 source
• Not checked yetcites [58] Harris SW Hessl D Goodlin-Jones B Ferranti J Bacalman S Barbato I Tassone F Hagerman PJ Herman H Hagerman RJ Autism profiles of males with fragile X syndrome Am J Ment Retard 113 427 438 2008 19127654 PMC2629645 source

In the paper

“BTBR T+tf/J (BTBR) is a commercially available inbred strain of mouse that displays behavioral phenotypes relevant to all three diagnostic symptoms of autism (60–62, 64, 66, 68–70, 72, 74–78).”

What the sources say

• Not checked yetcites [60] Bolivar VJ Walters SR Phoenix JL Assessing autism-like behavior in mice: Variations in social interactions among inbred strains Behav Brain Res 176 21 26 2007 17097158 PMC1831820 source
• Not checked yetcites [61] Moy SS Nadler JJ Young NB Perez A Holloway LP Barbaro RP Barbaro JR Wilson LM Threadgill DW Lauder JM Magnuson TR Crawley JN Mouse behavioral tasks relevant to autism: Phenotypes of 10 inbred strains Behav Brain Res 176 4 20 2007 16971002 PMC1857288 source
• Not checked yetcites [62] Yang M Zhodzishsky V Crawley JN Social deficits in BTBR T + tf/J mice are unchanged by cross-fostering with C57BL/6J mothers Int J Dev Neurosci 25 515 521 2007 17980995 PMC2194756 source
• Not checked yetcites [64] McFarlane HG Kusek GK Yang M Phoenix JL Bolivar VJ Crawley JN Autism-like behavioral phenotypes in BTBR T+tf/J mice Genes Brain Behav 7 152 163 2008 17559418 source
• Not checked yetcites [66] Scattoni ML Gandhy SU Ricceri L Crawley JN Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism PLoS One 3 e3067 2008 18728777 PMC2516927 source
• Not checked yetcites [68] Defensor EB Pearson BL Pobbe RL Bolivar VJ Blanchard DC Blanchard RJ A novel social proximity test suggests patterns of social avoidance and gaze aversion-like behavior in BTBR T+ tf/J mice Behav Brain Res 217 302 308 2011 21055421 PMC3124342 source
• Not checked yetcites [69] Pearson BL Pobbe RL Defensor EB Oasay L Bolivar VJ Blanchard DC Blanchard RJ Motor and cognitive stereotypies in the BTBR T+tf/J mouse model of autism Genes Brain Behav 10 228 235 2011 21040460 PMC3037433 source
• Not checked yetcites [70] Wöhr M Roullet FI Crawley JN Reduced scent marking and ultrasonic vocalizations in the BTBR T+tf/J mouse model of autism Genes Brain Behav 10 35 43 2011 20345893 PMC2903641 source
• Not checked yetcites [72] Silverman JL Tolu SS Barkan CL Crawley JN Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP Neuropsychopharmacology 35 976 989 2010 20032969 PMC2827881 source
• Not checked yetcites [74] Yang M Scattoni ML Zhodzishsky V Chen T Caldwell H Young WS McFarlane HG Crawley JN Social approach behaviors are similar on conventional versus reverse lighting cycles, and in replications across cohorts, in BTBR T+ tf/J, C57BL/6J, and vasopressin receptor 1B mutant mice Front Behav Neurosci 1 1 2007 18958184 PMC2525856 source

In the paper

“Several naturally occurring inbred strains of mice display behavioral features that recapitulate diagnostic symptoms of neurodevelopmental disorders (59–70).”

What the sources say

• Not checked yetcites [59] Sankoorikal GM Kaercher KA Boon CJ Lee JK Brodkin ES A mouse model system for genetic analysis of sociability: C57BL/6J versus BALB/cJ inbred mouse strains Biol Psychiatry 59 415 423 2006 16199013 source
• Not checked yetcites [60] Bolivar VJ Walters SR Phoenix JL Assessing autism-like behavior in mice: Variations in social interactions among inbred strains Behav Brain Res 176 21 26 2007 17097158 PMC1831820 source
• Not checked yetcites [61] Moy SS Nadler JJ Young NB Perez A Holloway LP Barbaro RP Barbaro JR Wilson LM Threadgill DW Lauder JM Magnuson TR Crawley JN Mouse behavioral tasks relevant to autism: Phenotypes of 10 inbred strains Behav Brain Res 176 4 20 2007 16971002 PMC1857288 source
• Not checked yetcites [62] Yang M Zhodzishsky V Crawley JN Social deficits in BTBR T + tf/J mice are unchanged by cross-fostering with C57BL/6J mothers Int J Dev Neurosci 25 515 521 2007 17980995 PMC2194756 source
• Not checked yetcites [63] Fairless AH Dow HC Toledo MM Malkus KA Edelmann M Li H Talbot K Arnold SE Abel T Brodkin ES Low sociability is associated with reduced size of the corpus callosum in the BALB/cJ inbred mouse strain Brain Res 1230 211 217 2008 18662677 PMC2629607 source
• Not checked yetcites [64] McFarlane HG Kusek GK Yang M Phoenix JL Bolivar VJ Crawley JN Autism-like behavioral phenotypes in BTBR T+tf/J mice Genes Brain Behav 7 152 163 2008 17559418 source
• Not checked yetcites [65] Moy SS Nadler JJ Poe MD Nonneman RJ Young NB Koller BH Crawley JN Duncan GE Bodfish JW Development of a mouse test for repetitive, restricted behaviors: Relevance to autism Behav Brain Res 188 178 194 2008 18068825 PMC2349090 source
• Not checked yetcites [66] Scattoni ML Gandhy SU Ricceri L Crawley JN Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism PLoS One 3 e3067 2008 18728777 PMC2516927 source
• Not checked yetcites [67] Ryan BC Young NB Crawley JN Bodfish JW Moy SS Social deficits, stereotypy and early emergence of repetitive behavior in the C58/J inbred mouse strain Behav Brain Res 208 178 188 2010 19941908 PMC2822076 source
• Not checked yetcites [68] Defensor EB Pearson BL Pobbe RL Bolivar VJ Blanchard DC Blanchard RJ A novel social proximity test suggests patterns of social avoidance and gaze aversion-like behavior in BTBR T+ tf/J mice Behav Brain Res 217 302 308 2011 21055421 PMC3124342 source

In the paper

“Experimentally induced postnatal lesions of the corpus callosum in B6 mice, however, did not recapitulate the social deficits, or the repetitive self-grooming, that characterize BTBR (82).”

What the sources say

• Not checked yetcites [82] Yang M Clarke AM Crawley JN Postnatal lesion evidence against a primary role for the corpus callosum in mouse sociability Eur J Neurosci 29 1663 1677 2009 19419429 PMC2762200 source

In the paper

“C58/J (C58) is another commercially available inbred strain of mouse that displays high levels of stereotyped vertical jumping behaviors, relevant to the motor stereotypies of the third diagnostic symptom category of autism (65, 67).”

What the sources say

• Not checked yetcites [65] Moy SS Nadler JJ Poe MD Nonneman RJ Young NB Koller BH Crawley JN Duncan GE Bodfish JW Development of a mouse test for repetitive, restricted behaviors: Relevance to autism Behav Brain Res 188 178 194 2008 18068825 PMC2349090 source
• Not checked yetcites [67] Ryan BC Young NB Crawley JN Bodfish JW Moy SS Social deficits, stereotypy and early emergence of repetitive behavior in the C58/J inbred mouse strain Behav Brain Res 208 178 188 2010 19941908 PMC2822076 source

In the paper

“Biological abnormalities have been reported in eye tracking, neuroanatomical pathway connectivity, brain regional volumes, cortical activation during social and communication tasks as measured with functional magnetic resonance imaging and magnetoencephalography, serotonin levels, and other biological assays, but not with sufficient consistency for these to constitute uniform diagnostic biomarkers”

What the sources say

• Not checked yetcites [92] Levy SE Mandell DS Schultz RT Autism Lancet 374 1627 1638 2009 19819542 PMC2863325 source
• Not checked yetcites [93] Bent S Hendren RL Improving the prediction of response to therapy in autism Neurotherapeutics 7 232 240 2010 20643375 PMC5084226 source
• Not checked yetcites [94] Veenstra-Vanderweele J Blakely RD Networking in autism: Leveraging genetic, biomarker and model system findings in the search for new treatments Neuropsychopharmacology 37 196 212 2012 21937981 PMC3238072 source

In the paper

“Lower self-grooming and jumping scores in the treated mice were not the result of overall behavioral sedation, because open field activity was not reduced by GRN-529 at the same doses, time point, and route of administration.”

In the paper

“Early clinical indications of beneficial actions of mGluR5 antagonists in fragile X syndrome make this class of therapeutic targets of particular interest (55).”

What the sources say

• Not checked yetcites [55] Krueger DD Bear MF Toward fulfilling the promise of molecular medicine in fragile X syndrome Annu Rev Med 62 411 429 2011 21090964 PMC3100156 source

In the paper

“The present preclinical findings on reversal of features relevant to autism in two mouse models convey promise for the mGluR5 strategy as a therapeutic intervention for two core diagnostic symptoms of autism.”