Cerebellar associative sensory learning defects in five mouse autism models

Abstract

Sensory integration difficulties have been reported in autism, but their underlying brain-circuit mechanisms are underexplored. Using five autism-related mouse models, Shank3+/ΔC, Mecp2R308/Y, Cntnap2−/−, L7-Tsc1 (L7/Pcp2Cre::Tsc1flox/+), and patDp(15q11-13)/+, we report specific perturbations in delay eyeblink conditioning, a form of associative sensory learning requiring cerebellar plasticity. By distinguishing perturbations in the probability and characteristics of learned responses, we found that probability was reduced in Cntnap2−/−, patDp(15q11-13)/+, and L7/Pcp2Cre::Tsc1flox/+, which are associated with Purkinje-cell/deep-nuclear gene expression, along with Shank3+/ΔC. Amplitudes were smaller in L7/Pcp2Cre::Tsc1flox/+ as well as Shank3+/ΔC and Mecp2R308/Y, which are associated with granule cell pathway expression. Shank3+/ΔC and Mecp2R308/Y also showed aberrant response timing and reduced Purkinje-cell dendritic spine density. Overall, our observations are potentially accounted for by defects in instructed learning in the olivocerebellar loop and response representation in the granule cell pathway. Our findings indicate that defects in associative temporal binding of sensory events are widespread in autism mouse models.DOI: http://dx.doi.org/10.7554/eLife.06085.001

Autism and cerebellar dysfunction: Evidence from animal models

“…In fact, we have demonstrated that many models of neurodevelopmental syndromes associated with ASD demonstrate abnormalities in cerebellar associative learning with abnormal eye-blink conditioning in mouse models with mutations in mecp2, shank3, cntnap2, or tsc1, or paternal 15q11-13 duplication [39]. Further evidence of a cerebellar contribution to ASD are discussed here in these monogenic neurodevelopmental disorders associated with high rates of ASD.…”

“…Moreover, ASD in TSC correlates with the presence of cerebellar lesions, whereas abnormal deep cerebellar nuclei function has been identified in patients with ASD and TSC [33,60]. In addition, we have demonstrated that mouse models of TSC display impairments in cerebellar eye-blink conditioning paradigms, further supporting roles for cerebellar dysfunction in the pathogenesis of ASD [39].…”

“…Rodent Shank3 models have autistic behaviors with social impairments, repetitive behaviors, abnormal vocalizations, and impaired learning [59]. These mice also demonstrate cerebellar anatomic abnormalities in addition to deficits in eye-blink conditioning [39,60]. With clear involvement of Shank3 in ASD behaviors and in cerebellar function, it will be important to define the precise impact of cerebellar Shank3 on ASD behaviors.…”

Intragenic CNTNAP2 Deletions: A Bridge Too Far

“…Cntnap2-null mice showed normal sensory responsiveness, gross motor function, and noncerebellar learning and memory functioning, but conditional responses and cerebellum-based learning were significantly reduced [Kloth et al, 2015]. In addition, they showed sig-nificant deficits in working and reference memory during acquisition of a task, while Cntnap2-null mice performed comparably to wild-type mice during the retention period [Rendall et al, 2016].…”

“…Studies of learning behavior and auditory processing in Cntnap2-null mice have generated novel insights relevant to ASD and other neurodevelopmental disorders [Kloth et al, 2015;Truong et al, 2015;Rendall et al, 2016]. These transgenic mice showed reduced silent gap detection but superior pitch-related discrimination as compared to wild-type controls.…”