Behavioural Brain Research 196 (2009) 297–303 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report Interstimulus interval (ISI) discrimination of the conditioned eyeblink response in a rodent model of autism Nathen J. Murawski, Kevin L. Brown, Mark E. Stanton ∗ Department of Psychology, University of Delaware, Newark, DE 19716, United States article info Article history: Received 2 April 2008 Received in revised form 14 September 2008 Accepted 19 September 2008 Available online 2 October 2008 Keywords: Autism Cerebellum Developmental neurotoxicology Classical conditioning Valproate Temporal processing Response timing Brainstem abstract Rats exposed to valproic acid (VPA) on gestational day 12 (GD12) have been advanced as a rodent model of autism [Arndt TL, Stodgell, Rodier PM. The teratology of autism. Int J Dev Neurosci 2005;23: 189–99.]. These rats show cerebellar anomalies and alterations in eyeblink conditioning that are associated with autism. Autistic humans and VPA-exposed rats show normal responses to conditioned and unconditioned stimuli, but they show marked differences from comparison groups in acquisition, magnitude, and timing of the conditioned response (CR). This study examined VPA-induced eyeblink CR timing differences by training rats on an interstimulus interval (ISI) discrimination task, in which two distinct conditioned stimuli (CS; tone and light) are paired with the same unconditioned stimulus (US; periocular shock) at two distinct CS–US intervals. Previous findings suggest that this task would produce abnormally large and prematurely timed CRs for VPA-exposed rats relative to controls. Adult male Long-Evans rats that were exposed to either VPA or saline on GD 12.5 were trained on an ISI discrimination task [Brown KL, Pagani JH, Stanton ME. The ontogeny of interstimulus interval (ISI) discrimination of the conditioned eyeblink response in rats. Behav Neurosci 2006;120: 1057–70.]. In support of earlier findings, we observed early acquisition and enhanced magnitude of the CR in VPA rats compared with controls on long CS trials. VPA rats also showed prematurely timed CRs to long- CS trials, but not to short- CS trials. The ISI discrimination procedure used in the current study reveals differential timed responses in this animal model of autism not previously seen. © 2008 Elsevier B.V. All rights reserved. Autism spectrum disorder (ASD) is characterized by social and language impairments, and restricted or repetitive behaviors [1]. The incidence of ASDs is on the increase and recent reports suggest an overall prevalence of 6.7 per 1000 children aged 8 years [9]. Reports concerning an increased incidence of autism in the offspring of mothers exposed to the specific teratogens thalidomide [47,48] and valproic acid (VPA) [12] during the 1st trimester supports the hypothesis that early gestational injury to the brainstem plays a role in the etiology of autism [39]. The gestational day (GD) 12.5 VPA animal model of autism devel- oped by Rodier et al. [39] also gives support to this hypothesis. Rats exposed to VPA on GD 12.5 show neuroanatomical abnor- malities which parallel those in human cases of autism [39]. Specifically, VPA-exposed rats have an overall reduction of cere- bellar and posterior vermis volume, of Purkinje cells in both ∗ Corresponding author at: Wolf 132, Department of Psychology. University of Delaware, Newark, DE 19716, United States. Tel.: +1 302 831 0575; fax: +1 302 831 3645. E-mail address: Stanton@psych.udel.edu (M.E. Stanton). the cerebellar hemispheres and posterior vermis [19], of neurons in the interpositus nucleus [4] as well as neurons in brain- stem motor nuclei [39]. The advent of a rodent model of autism based on common developmental etiology and neuroanatom- ical phenotype creates an opportunity to examine behavioral parallels between this animal model and the human disorder [3,37,38,46]. As pointed out by Stanton et al. [46], eyeblink conditioning (EBC) offers a number of advantages as a behavioral test of a rodent model of autism. First, an identified brainstem-cerebellar circuit is essential for the acquisition and maintenance of delay EBC (for a review see ref. [49]). Second, the neuroanatomical abnormali- ties present in autistic patients and in the GD 12.5 VPA animal model overlap with the brainstem-cerebellar circuit mediating EBC [3,8,15,18,19,39,40]. Third, the necessary and sufficient circuitry underlying EBC is conserved across mammalian species [51,52]. And fourth, EBC conducted in human cases of autism reveal a unique phenotype of conditioned response (CR) acquisition and timing [41]. EBC within the VPA model, therefore, can reveal how early brainstem-cerebellar injury affects subsequent performance on this behavioral task, which allows for inferences to be made con- 0166-4328/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2008.09.020