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Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism

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Abstract

Rationale

Abnormalities in excitatory/inhibitory neurotransmission are hypothesized to contribute to autism spectrum disorder (ASD) etiology. BTBR T + Itpr3 tf/J (BTBR), an inbred mouse strain, displays social deficits and repetitive self-grooming, offering face validity to ASD diagnostic symptoms. Reduced GABAergic neurotransmission in BTBR suggests that GABAA receptor positive allosteric modulators (PAMs) could improve ASD-relevant BTBR phenotypes. The neuroactive steroid ganaxolone acts as a PAM, displaying anticonvulsant properties in rodent epilepsy models and an anxiolytic-like profile in the elevated plus-maze.

Objectives

We evaluated ganaxolone in BTBR and C57BL/6J mice in standardized assays for sociability and repetitive behaviors. Open field and anxiety-related behaviors were tested as internal controls and for comparison with the existing neuroactive steroid literature.

Results

Ganaxolone improved aspects of social approach and reciprocal social interactions in BTBR, with no effect on repetitive self-grooming, and no detrimental effects in C57BL/6J. Ganaxolone increased overall exploratory activity in BTBR and C57BL/6J in the open field, social approach, and elevated plus-maze, introducing a confound for the interpretation of social improvements. Allopregnanolone and diazepam similarly increased total entries in the elevated plus-maze, indicating that behavioral activation may be a general property of GABAA receptor PAMs in these strains.

Conclusions

Ganaxolone shows promise for improving sociability. In addition, ganaxolone, as well as other GABAA receptor PAMs, enhanced overall BTBR activity. The translational implications of specific sociability improvements and nonspecific behavioral activation by ganaxolone in the BTBR model remain to be determined. Future studies to explore whether PAMs provide a novel profile with unique benefits for ASD treatment will be worthwhile.

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References

  • Abbeduto L, McDuffie A, Thurman AJ (2014) The fragile X syndrome-autism comorbidity: what do we really know? Front Genet 5:355

    Article  PubMed  PubMed Central  Google Scholar 

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Publishing, Washington

    Google Scholar 

  • Bailey DB Jr, Mesibov GB, Hatton DD, Clark RD, Roberts JE, Mayhew L (1998) Autistic behavior in young boys with fragile X syndrome. J Autism Dev Disord 28:499–508

    Article  PubMed  Google Scholar 

  • Beekman M, Ungard JT, Gasior M, Carter RB, Dijkstra D, Goldberg SR, Witkin JM (1998) Reversal of behavioral effects of pentylenetetrazol by the neuroactive steroid ganaxolone. J Pharmacol Exp Ther 284:868–877

    PubMed  CAS  Google Scholar 

  • Belelli D, Lambert JJ (2005) Neurosteroids: endogenous regulators of the GABAA receptor. Nat Rev Neurosci 6:565–575

    Article  PubMed  CAS  Google Scholar 

  • Bertram EH, Lothman EW (1990) NMDA receptor antagonists and limbic status epilepticus: a comparison with standard anticonvulsants. Epilepsy Res 5:177–184

    Article  PubMed  CAS  Google Scholar 

  • Bitran D, Hilvers RJ, Kellogg CK (1991) Anxiolytic effects of 3 alpha-hydroxy-5 alpha[beta]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Res 561:157–161

    Article  PubMed  CAS  Google Scholar 

  • Blanchard DC, Defensor EB, Meyza KZ, Pobbe RL, Pearson BL, Bolivar VJ, Blanchard RJ (2012) BTBR T+tf/J mice: autism-relevant behaviors and reduced fractone-associated heparan sulfate. Neurosci Biobehav Rev 36:285–296

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bolivar VJ, Walters SR, Phoenix JL (2007) Assessing autism-like behavior in mice: variations in social interactions among inbred strains. Behav Brain Res 176:21–26

    Article  PubMed  PubMed Central  Google Scholar 

  • Brielmaier J, Senerth JM, Silverman JL, Matteson PG, Millonig JH, DiCicco-Bloom E, Crawley JN (2014) Chronic desipramine treatment rescues depression-related, social and cognitive deficits in engrailed-2 knockout mice. Genes Brain Behav 13:286–298

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Burket JA, Benson AD, Tang AH, Deutsch SI (2013) D-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling. Brain Res Bull 96:62–70

    Article  PubMed  CAS  Google Scholar 

  • Buxbaum JD, Silverman JM, Smith CJ, Greenberg DA, Kilifarski M, Reichert J, Cook EH Jr, Fang Y, Song CY, Vitale R (2002) Association between a GABRB3 polymorphism and autism. Mol Psychiatry 7:311–316

    Article  PubMed  CAS  Google Scholar 

  • Cardinal RN, Parkinson JA, Hall J, Everitt BJ (2002) Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neurosci Biobehav Rev 26:321–352

    Article  PubMed  Google Scholar 

  • Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf HH, Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW (1997) Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid (A) receptor. J Pharmacol Exp Ther 280:1284–1295

    PubMed  CAS  Google Scholar 

  • Cole JC, Rodgers RJ (1995) Ethological comparison of the effects of diazepam and acute/chronic imipramine on the behaviour of mice in the elevated plus-maze. Pharmacol Biochem Behav 52:473–478

    Article  PubMed  CAS  Google Scholar 

  • Crawley JN (1985) Exploratory behavior models of anxiety in mice. Neurosci Biobehav Rev 9:37–44

    Article  PubMed  CAS  Google Scholar 

  • Crawley JN, Davis LG (1982) Baseline exploratory activity predicts anxiolytic responsiveness to diazepam in five mouse strains. Brain Res Bull 8:609–612

    Article  PubMed  CAS  Google Scholar 

  • Dalvi A, Rodgers RJ (1999) Behavioral effects of diazepam in the murine plus-maze: flumazenil antagonism of enhanced head dipping but not the disinhibition of open-arm avoidance. Pharmacol Biochem Behav 62:727–734

    Article  PubMed  CAS  Google Scholar 

  • Darbra S, Pallares M (2012) Effects of early postnatal allopregnanolone administration on elevated plus maze anxiety scores in adult male Wistar rats. Neuropsychobiology 65:20–27

    Article  PubMed  CAS  Google Scholar 

  • Distler MG, Gorfinkle N, Papale LA, Wuenschell GE, Termini J, Escayg A, Winawer MR, Palmer AA (2013) Glyoxalase 1 and its substrate methylglyoxal are novel regulators of seizure susceptibility. Epilepsia 54:649–657

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Dubrovsky BO (2005) Steroids, neuroactive steroids and neurosteroids in psychopathology. Prog Neuro-Psychopharmacol Biol Psychiatry 29:169–192

    Article  CAS  Google Scholar 

  • Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcin C, Montiel-Nava C, Patel V, Paula CS, Wang C, Yasamy MT, Fombonne E (2012) Global prevalence of autism and other pervasive developmental disorders. Autism Res Off J Int Soc Autism Res 5:160–179

    Article  Google Scholar 

  • Evans J, Sun Y, McGregor A, Connor B (2012) Allopregnanolone regulates neurogenesis and depressive/anxiety-like behaviour in a social isolation rodent model of chronic stress. Neuropharmacology 63:1315–1326

    Article  PubMed  CAS  Google Scholar 

  • File SE, Lippa AS, Beer B, Lippa MT (2004) Animal tests of anxiety. Current protocols in neuroscience/editorial board, Jacqueline N Crawley [et al.] Chapter 8: Unit 8 3

  • Flannery BM, Silverman JL, Bruun DA, Puhger KR, McCoy MR, Hammock BD, Crawley JN, Lein PJ (2015) Behavioral assessment of NIH Swiss mice acutely intoxicated with tetramethylenedisulfotetramine. Neurotoxicol Teratol 47:36–45

    Article  PubMed  CAS  Google Scholar 

  • Garrett KM, Niekrasz I, Haque D, Parker KM, Seale TW (1998) Genotypic differences between C57BL/6 and A inbred mice in anxiolytic and sedative actions of diazepam. Behav Genet 28:125–136

    Article  PubMed  CAS  Google Scholar 

  • Gasior M, Ungard JT, Beekman M, Carter RB, Witkin JM (2000) Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: comparison with diazepam and valproate. Neuropharmacology 39:1184–1196

    Article  PubMed  CAS  Google Scholar 

  • Gogolla N, Takesian AE, Feng G, Fagiolini M, Hensch TK (2014) Sensory integration in mouse insular cortex reflects GABA circuit maturation. Neuron 83:894–905

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Gould GG, Hensler JG, Burke TF, Benno RH, Onaivi ES, Daws LC (2011) Density and function of central serotonin (5-HT) transporters, 5-HT1A and 5-HT2A receptors, and effects of their targeting on BTBR T+tf/J mouse social behavior. J Neurochem 116:291–303

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Griebel G, Belzung C, Perrault G, Sanger DJ (2000) Differences in anxiety-related behaviours and in sensitivity to diazepam in inbred and outbred strains of mice. Psychopharmacology 148:164–170

    Article  PubMed  CAS  Google Scholar 

  • Hagerman RJ, Jackson AW 3rd, Levitas A, Rimland B, Braden M (1986) An analysis of autism in fifty males with the fragile X syndrome. Am J Med Genet 23:359–374

    Article  PubMed  CAS  Google Scholar 

  • Han S, Tai C, Jones CJ, Scheuer T, Catterall WA (2014) Enhancement of inhibitory neurotransmission by GABAA receptors having alpha2,3-subunits ameliorates behavioral deficits in a mouse model of autism. Neuron 81:1282–1289

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Harris SW, Hessl D, Goodlin-Jones B, Ferranti J, Bacalman S, Barbato I, Tassone F, Hagerman PJ, Herman H, Hagerman RJ (2008) Autism profiles of males with fragile X syndrome. Am J Ment Retard AJMR 113:427–438

    Article  PubMed  Google Scholar 

  • Helton DR, Berger JE, Czachura JF, Rasmussen K, Kallman MJ (1996) Central nervous system characterization of the new cholecystokininB antagonist LY288513. Pharmacol Biochem Behav 53:493–502

    Article  PubMed  CAS  Google Scholar 

  • Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ (1998) Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. J Pharmacol Exp Ther 284:651–660

    PubMed  CAS  Google Scholar 

  • Heulens I, D’Hulst C, Van Dam D, De Deyn PP, Kooy RF (2012) Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model. Behav Brain Res 229:244–249

    Article  PubMed  CAS  Google Scholar 

  • Hogart A, Nagarajan RP, Patzel KA, Yasui DH, Lasalle JM (2007) 15q11-13 GABAA receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism-spectrum disorders. Hum Mol Genet 16:691–703

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hogart A, Leung KN, Wang NJ, Wu DJ, Driscoll J, Vallero RO, Schanen NC, LaSalle JM (2009) Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J Med Genet 46:86–93

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hogenkamp DJ, Tran MB, Yoshimura RF, Johnstone TB, Kanner R, Gee KW (2014) Pharmacological profile of a 17beta-heteroaryl-substituted neuroactive steroid. Psychopharmacology 231:3517–3524

    Article  PubMed  CAS  Google Scholar 

  • Hosie AM, Wilkins ME, da Silva HM, Smart TG (2006) Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 444:486–489

    Article  PubMed  CAS  Google Scholar 

  • Johnson NJ, Rodgers RJ (1996) Ethological analysis of cholecystokinin (CCKA and CCKB) receptor ligands in the elevated plus-maze test of anxiety in mice. Psychopharmacology 124:355–364

    Article  PubMed  CAS  Google Scholar 

  • Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, Cheon KA, Kim SJ, Kim YK, Lee H, Song DH, Grinker RR (2011) Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry 168:904–912

    Article  PubMed  Google Scholar 

  • Kooy F, Heulens I, Sabanov V, Ahmed T, Popp A, Willemsen R, D'Hooge R, Baltschun D, Rooms L (2013) Hippocampal defects in the Fmr1 knockout mouse, American Society of Human Genetics

  • Kuraoka K, Nakamura K (2006) Impacts of facial identity and type of emotion on responses of amygdala neurons. Neuroreport 17:9–12

    Article  PubMed  Google Scholar 

  • LaBuda CJ, Fuchs PN (2001) The anxiolytic effect of acute ethanol or diazepam exposure is unaltered in mu-opioid receptor knockout mice. Brain Res Bull 55:755–760

    Article  PubMed  CAS  Google Scholar 

  • Lambert JJ, Belelli D, Hill-Venning C, Peters JA (1995) Neurosteroids and GABAA receptor function. Trends Pharmacol Sci 16:295–303

    Article  PubMed  CAS  Google Scholar 

  • Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA (2003) Neurosteroid modulation of GABAA receptors. Prog Neurobiol 71:67–80

    Article  PubMed  CAS  Google Scholar 

  • Lepicard EM, Joubert C, Hagneau I, Perez-Diaz F, Chapouthier G (2000) Differences in anxiety-related behavior and response to diazepam in BALB/cByJ and C57BL/6J strains of mice. Pharmacol Biochem Behav 67:739–748

    Article  PubMed  CAS  Google Scholar 

  • Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185

    PubMed  CAS  Google Scholar 

  • McDuffie A, Thurman AJ, Hagerman RJ, Abbeduto L (2014) Symptoms of autism in males with fragile X syndrome: a comparison to nonsyndromic ASD using current ADI-R scores. J Autism Dev Disord

  • McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN (2008) Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav 7:152–163

    Article  PubMed  CAS  Google Scholar 

  • Modol L, Darbra S, Pallares M (2011) Neurosteroids infusion into the CA1 hippocampal region on exploration, anxiety-like behaviour and aversive learning. Behav Brain Res 222:223–229

    Article  PubMed  CAS  Google Scholar 

  • Morrow AL (2007) Recent developments in the significance and therapeutic relevance of neuroactive steroids—introduction to the special issue. Pharmacol Ther 116:1–6

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP, Barbaro JR, Wilson LM, Threadgill DW, Lauder JM, Magnuson TR, Crawley JN (2007) Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res 176:4–20

    Article  PubMed  PubMed Central  Google Scholar 

  • Murray EA (2007) The amygdala, reward and emotion. Trends Cogn Sci 11:489–497

    Article  PubMed  Google Scholar 

  • Oakley JC, Cho AR, Cheah CS, Scheuer T, Catterall WA (2013) Synergistic GABA-enhancing therapy against seizures in a mouse model of Dravet syndrome. J Pharmacol Exp Ther 345:215–224

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Paul SM, Purdy RH (1992) Neuroactive steroids. FASEB J Off Publ Fed Am Soc Exp Biol 6:2311–2322

    CAS  Google Scholar 

  • Phelps EA (2006) Emotion and cognition: insights from studies of the human amygdala. Annu Rev Psychol 57:27–53

    Article  PubMed  Google Scholar 

  • Pinna G, Rasmusson AM (2014) Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder. Front Cell Neurosci 8:256

    Article  PubMed  PubMed Central  Google Scholar 

  • Pobbe RL, Pearson BL, Defensor EB, Bolivar VJ, Blanchard DC, Blanchard RJ (2010) Expression of social behaviors of C57BL/6J versus BTBR inbred mouse strains in the visible burrow system. Behav Brain Res 214:443–449

    Article  PubMed  PubMed Central  Google Scholar 

  • Pobbe RL, Defensor EB, Pearson BL, Bolivar VJ, Blanchard DC, Blanchard RJ (2011) General and social anxiety in the BTBR T+ tf/J mouse strain. Behav Brain Res 216:446–451

    Article  PubMed  PubMed Central  Google Scholar 

  • Reddy DS (2013) Neuroendocrine aspects of catamenial epilepsy. Horm Behav 63:254–266

    Article  PubMed  CAS  Google Scholar 

  • Reddy DS, Rogawski MA (2010) Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model. Epilepsy Res 89:254–260

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Reddy DS, Rogawski MA (2012) Neurosteroids—endogenous regulators of seizure susceptibility and role in the treatment of epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies, Bethesda (MD)

  • Reddy DS, Castaneda DC, O’Malley BW, Rogawski MA (2004) Anticonvulsant activity of progesterone and neurosteroids in progesterone receptor knockout mice. J Pharmacol Exp Ther 310:230–239

    Article  PubMed  CAS  Google Scholar 

  • Reddy DS, O’Malley BW, Rogawski MA (2005) Anxiolytic activity of progesterone in progesterone receptor knockout mice. Neuropharmacology 48:14–24

    Article  PubMed  CAS  Google Scholar 

  • Rodgers RJ, Johnson NJ (1998) Behaviorally selective effects of neuroactive steroids on plus-maze anxiety in mice. Pharmacol Biochem Behav 59:221–232

    Article  PubMed  CAS  Google Scholar 

  • Rodgers RJ, Lee C, Shepherd JK (1992) Effects of diazepam on behavioural and antinociceptive responses to the elevated plus-maze in male mice depend upon treatment regimen and prior maze experience. Psychopharmacology 106:102–110

    Article  PubMed  CAS  Google Scholar 

  • Rogers SJ, Wehner DE, Hagerman R (2001) The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. J Dev Behav Pediatr JDBP 22:409–417

    Article  PubMed  CAS  Google Scholar 

  • Romo-Parra H, Blaesse P, Sosulina L, Pape HC (2015) Neurosteroids increase tonic GABAergic inhibition in the lateral section of the central amygdala in mice. J Neurophysiol: JN 00045 2015

  • Rubenstein JL, Merzenich MM (2003) Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2:255–267

    Article  PubMed  CAS  Google Scholar 

  • Rundfeldt C, Wlaz P, Honack D, Loscher W (1995) Anticonvulsant tolerance and withdrawal characteristics of benzodiazepine receptor ligands in different seizure models in mice. Comparison of diazepam, bretazenil and abecarnil. J Pharmacol Exp Ther 275:693–702

    PubMed  CAS  Google Scholar 

  • Scattoni ML, Ricceri L, Crawley JN (2011) Unusual repertoire of vocalizations in adult BTBR T+tf/J mice during three types of social encounters. Genes Brain Behav 10:44–56

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Silverman JL, Tolu SS, Barkan CL, Crawley JN (2010) Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 35:976–989

    Article  CAS  Google Scholar 

  • Silverman JL, Smith DG, Rizzo SJ, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley JN (2012) Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. Sci Transl Med 4:131ra51

    PubMed  Google Scholar 

  • Silverman JL, Oliver CF, Karras MN, Gastrell PT, Crawley JN (2013) AMPAKINE enhancement of social interaction in the BTBR mouse model of autism. Neuropharmacology 64:268–282

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Silverman JL, Pride MC, Hayes JE, Puhger KR, Butler-Struben H, Baker S, 'Crawley JN (2015) GABA receptor agonist R-baclofen reverses social deficits and reduces repetitive behavior in two mouse models of autism. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol

  • Thompson T, Grabowski-Boase L, Tarantino LM (2015) Prototypical anxiolytics do not reduce anxiety-like behavior in the open field in C57BL/6J mice. Pharmacol Biochem Behav 133:7–17

    Article  PubMed  CAS  Google Scholar 

  • Thurman AJ, McDuffie A, Kover ST, Hagerman RJ, Abbeduto L (2015) Autism symptomatology in boys with fragile X syndrome: a cross sectional developmental trajectories comparison with nonsyndromic autism spectrum disorder. J Autism Dev Disord

  • Treiman DM (2001) GABAergic mechanisms in epilepsy. Epilepsia 42(Suppl 3):8–12

    Article  PubMed  Google Scholar 

  • Ungard JT, Beekman M, Gasior M, Carter RB, Dijkstra D, Witkin JM (2000) Modification of behavioral effects of drugs in mice by neuroactive steroids. Psychopharmacology 148:336–343

    Article  PubMed  CAS  Google Scholar 

  • Wang M (2011) Neurosteroids and GABA-A receptor function. Front Endocrinol 2:44

    Article  Google Scholar 

  • Wieland S, Belluzzi JD, Stein L, Lan NC (1995) Comparative behavioral characterization of the neuroactive steroids 3 alpha-OH,5 alpha-pregnan-20-one and 3 alpha-OH,5 beta-pregnan-20-one in rodents. Psychopharmacology 118:65–71

    Article  PubMed  CAS  Google Scholar 

  • Wieland S, Belluzzi J, Hawkinson JE, Hogenkamp D, Upasani R, Stein L, Wood PL, Gee KW, Lan NC (1997) Anxiolytic and anticonvulsant activity of a synthetic neuroactive steroid Co 3-0593. Psychopharmacology 134:46–54

    Article  PubMed  CAS  Google Scholar 

  • Yang M, Zhodzishsky V, Crawley JN (2007) Social deficits in BTBR T+tf/J mice are unchanged by cross-fostering with C57BL/6J mothers. Int J Dev Neurosci Off J Int Soc Dev Neurosci 25:515–521

    Article  Google Scholar 

  • Yang M, Perry K, Weber MD, Katz AM, Crawley JN (2011a) Social peers rescue autism-relevant sociability deficits in adolescent mice. Autism Res Off J Int Soc Autism Res 4:17–27

    Article  Google Scholar 

  • Yang M, Silverman JL, Crawley JN (2011b) Automated three-chambered social approach task for mice. Current protocols in neuroscience/editorial board, Jacqueline N Crawley [et al.] Chapter 8: Unit 8 26

  • Yang M, Loureiro D, Kalikhman D, Crawley JN (2013) Male mice emit distinct ultrasonic vocalizations when the female leaves the social interaction arena. Front Behav Neurosci 7:159

  • Zhang WQ, Smolik CM, Barba-Escobedo PA, Gamez M, Sanchez JJ, Javors MA, Daws LC, Gould GG (2015) Acute dietary tryptophan manipulation differentially alters social behavior, brain serotonin and plasma corticosterone in three inbred mouse strains. Neuropharmacology 90:1–8

    Article  PubMed  Google Scholar 

  • Zimmerberg B, Martinez AR, Skudder CM, Killien EY, Robinson SA, Brunelli SA (2010) Effects of gestational allopregnanolone administration in rats bred for high affective behavior. Physiol Behav 99:212–217

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the UC Davis MIND Institute, the Autism Research Training Program (NIH/NIMH Grant T32 MH073124-10, Interdisciplinary Training for Autism Researchers), and the MIND Institute Intellectual and Developmental Disabilities Research Center (U54 HD079125). We thank Lisa Olsen in the Rogawski lab for her kind assistance in providing compounds and vehicles. In addition, we thank Dr. Jill Silverman, Dr. Mu Yang, Michael Pride, and Jane Hayes, UC Davis MIND Institute investigators in the Crawley lab, for their training on specific methods used by Dr. Kazdoba in the behavioral assays and statistical analyses of the data.

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Authors and Affiliations

  1. MIND Institute, Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, 95817, USA

    Tatiana M. Kazdoba & Jacqueline N. Crawley

  2. MIND Institute, Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, USA

    Randi J. Hagerman

  3. Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, USA

    Dorota Zolkowska & Michael A. Rogawski

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  1. Tatiana M. Kazdoba
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Correspondence to Tatiana M. Kazdoba.

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All procedures were conducted in compliance with the NIH Guidelines for the Care and Use of Laboratory Animals and approved by the UC Davis Institutional Animal Care and Use Committee.

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Dr. Hagerman has received funding from the Department of Defense and from Marinus Pharmaceuticals to study ganaxolone in a controlled trial in fragile X syndrome, both with and without autism. Dr. Rogawski is a consultant to Sage Therapeutics. Drs. Kazdoba, Zolkowska, and Crawley declare that they have no competing interests.

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Kazdoba, T.M., Hagerman, R.J., Zolkowska, D. et al. Evaluation of the neuroactive steroid ganaxolone on social and repetitive behaviors in the BTBR mouse model of autism. Psychopharmacology 233, 309–323 (2016). https://doi.org/10.1007/s00213-015-4115-7

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