Cerebellar associative sensory learning defects in five mouse autism models

Alexander D. Kloth, Aleksandra Badura, Amy Li, Adriana Cherskov, Sara G. Connolly, Andrea Giovannucci, M. Ali Bangash, Giorgio Grasselli, Olga Peñ Agarikano, Claire Piochon, Peter T. Tsai, Daniel H. Geschwind, Christian Hansel, Mustafa Sahin, Toru Takumi, Paul F. Worley, Samuel S H Wang

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Sensory integration difficulties have been reported in autism, but their underlying braincircuit mechanisms are underexplored. Using five autism-related mouse models, Shank3+/ΔC, Mecp2R308/Y, Cntnap2−/−, L7-Tsc1 (L7/Pcp2<sup>Cre</sup>::Tsc1<sup>flox/+</sup>), 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/Pcp2<sup>Cre</sup>::Tsc1<sup>flox/+</sup>, which are associated with Purkinje-cell/deep-nuclear gene expression, along with Shank3+/ΔC. Amplitudes were smaller in L7/Pcp2<sup>Cre</sup>::Tsc1<sup>flox/+</sup> as well as Shank3+/ΔC and Mecp2<sup>R308/Y</sup>, which are associated with granule cell pathway expression. Shank3+/ΔC and Mecp2<sup>R308/Y</sup> 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.

Original languageEnglish (US)
Article numbere06085
JournaleLife
Volume4
Issue numberJULY 2015
DOIs
StatePublished - Jul 9 2015

Fingerprint

Autistic Disorder
Purkinje Cells
Learning
Defects
Gene expression
Plasticity
Dendritic Spines
Gene Expression
Dendritic Cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Medicine(all)
  • Neuroscience(all)

Cite this

Kloth, A. D., Badura, A., Li, A., Cherskov, A., Connolly, S. G., Giovannucci, A., ... Wang, S. S. H. (2015). Cerebellar associative sensory learning defects in five mouse autism models. eLife, 4(JULY 2015), [e06085]. https://doi.org/10.7554/eLife.06085

Cerebellar associative sensory learning defects in five mouse autism models. / Kloth, Alexander D.; Badura, Aleksandra; Li, Amy; Cherskov, Adriana; Connolly, Sara G.; Giovannucci, Andrea; Bangash, M. Ali; Grasselli, Giorgio; Agarikano, Olga Peñ; Piochon, Claire; Tsai, Peter T.; Geschwind, Daniel H.; Hansel, Christian; Sahin, Mustafa; Takumi, Toru; Worley, Paul F.; Wang, Samuel S H.

In: eLife, Vol. 4, No. JULY 2015, e06085, 09.07.2015.

Research output: Contribution to journalArticle

Kloth, AD, Badura, A, Li, A, Cherskov, A, Connolly, SG, Giovannucci, A, Bangash, MA, Grasselli, G, Agarikano, OP, Piochon, C, Tsai, PT, Geschwind, DH, Hansel, C, Sahin, M, Takumi, T, Worley, PF & Wang, SSH 2015, 'Cerebellar associative sensory learning defects in five mouse autism models', eLife, vol. 4, no. JULY 2015, e06085. https://doi.org/10.7554/eLife.06085
Kloth AD, Badura A, Li A, Cherskov A, Connolly SG, Giovannucci A et al. Cerebellar associative sensory learning defects in five mouse autism models. eLife. 2015 Jul 9;4(JULY 2015). e06085. https://doi.org/10.7554/eLife.06085
Kloth, Alexander D. ; Badura, Aleksandra ; Li, Amy ; Cherskov, Adriana ; Connolly, Sara G. ; Giovannucci, Andrea ; Bangash, M. Ali ; Grasselli, Giorgio ; Agarikano, Olga Peñ ; Piochon, Claire ; Tsai, Peter T. ; Geschwind, Daniel H. ; Hansel, Christian ; Sahin, Mustafa ; Takumi, Toru ; Worley, Paul F. ; Wang, Samuel S H. / Cerebellar associative sensory learning defects in five mouse autism models. In: eLife. 2015 ; Vol. 4, No. JULY 2015.
@article{324005c249014d5fac2bf128a179ee0d,
title = "Cerebellar associative sensory learning defects in five mouse autism models",
abstract = "Sensory integration difficulties have been reported in autism, but their underlying braincircuit 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.",
author = "Kloth, {Alexander D.} and Aleksandra Badura and Amy Li and Adriana Cherskov and Connolly, {Sara G.} and Andrea Giovannucci and Bangash, {M. Ali} and Giorgio Grasselli and Agarikano, {Olga Pe{\~n}} and Claire Piochon and Tsai, {Peter T.} and Geschwind, {Daniel H.} and Christian Hansel and Mustafa Sahin and Toru Takumi and Worley, {Paul F.} and Wang, {Samuel S H}",
year = "2015",
month = "7",
day = "9",
doi = "10.7554/eLife.06085",
language = "English (US)",
volume = "4",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
number = "JULY 2015",

}

TY - JOUR

T1 - Cerebellar associative sensory learning defects in five mouse autism models

AU - Kloth, Alexander D.

AU - Badura, Aleksandra

AU - Li, Amy

AU - Cherskov, Adriana

AU - Connolly, Sara G.

AU - Giovannucci, Andrea

AU - Bangash, M. Ali

AU - Grasselli, Giorgio

AU - Agarikano, Olga Peñ

AU - Piochon, Claire

AU - Tsai, Peter T.

AU - Geschwind, Daniel H.

AU - Hansel, Christian

AU - Sahin, Mustafa

AU - Takumi, Toru

AU - Worley, Paul F.

AU - Wang, Samuel S H

PY - 2015/7/9

Y1 - 2015/7/9

N2 - Sensory integration difficulties have been reported in autism, but their underlying braincircuit 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.

AB - Sensory integration difficulties have been reported in autism, but their underlying braincircuit 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.

UR - http://www.scopus.com/inward/record.url?scp=84938355964&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938355964&partnerID=8YFLogxK

U2 - 10.7554/eLife.06085

DO - 10.7554/eLife.06085

M3 - Article

VL - 4

JO - eLife

JF - eLife

SN - 2050-084X

IS - JULY 2015

M1 - e06085

ER -