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Decreased Expression of Synaptophysin 1 (SYP1 Major Synaptic Vesicle Protein p38) and Contactin 6 (CNTN6/NB3) in the Cerebellar Vermis of reln Haplodeficient Mice

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Abstract

Reeler heterozygous mice (reln+/−) are seemingly normal but haplodeficient in reln, a gene implicated in autism. Structural/neurochemical alterations in the reln+/− brain are subtle and difficult to demonstrate. Therefore, the usefulness of these mice in translational research is still debated. As evidence implicated several synapse-related genes in autism and the cerebellar vermis is structurally altered in the condition, we have investigated the expression of synaptophysin 1 (SYP1) and contactin 6 (CNTN6) within the vermis of reln+/− mice. Semi-thin plastic sections of the vermis from adult mice of both sexes and different genotypes (reln+/− and reln+/+) were processed with an indirect immunofluorescence protocol. Immunofluorescence was quantified on binary images and statistically analyzed. Reln+/− males displayed a statistically significant reduction of 11.89% in the expression of SYP1 compared to sex-matched wild-type animals, whereas no differences were observed between reln+/+ and reln+/− females. In reln+/− male mice, reductions were particularly evident in the molecular layer: 10.23% less SYP1 than reln+/+ males and 5.84% < reln+/+ females. In reln+/− females, decrease was 9.84% versus reln+/+ males and 5.43% versus reln+/+ females. Both reln+/− males and females showed a stronger decrease in CNTN6 expression throughout all the three cortical layers of the vermis: 17–23% in the granular layer, 24-26% in the Purkinje cell layer, and 9–14% in the molecular layer. Altogether, decrease of vermian SYP1 and CNTN6 in reln+/− mice displayed patterns compatible with the structural modifications of the autistic cerebellum. Therefore, these mice may be a good model in translational studies.

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Abbreviations

BSA:

Bovine serum albumin

CI:

Confidence interval

CNTN6:

Contactin 6

DAPI:

4′,6-diamidino-2-phenylindole

GL:

Granular layer of the cerebellar cortex

HET:

Heterozygous

IQ:

Intelligence quotient

ML:

Molecular layer of the cerebellar cortex

NGS:

Normal goat serum

PFA:

Percentage of the fluorescent area

PF-PN:

Parallel fiber-to-Purkinje neuron

PL:

Purkinje cells’ layer of the cerebellar cortex

PPI:

Pre-pulse inhibition

RELN :

Reelin gene (human)

RELN:

Reelin glycoprotein (human)

Reln :

Reelin gene (mouse)

Reln:

Reelin glycoprotein (mouse)

ROI:

Region of interest

sMRI:

Structural magnetic resonance imaging

SYP1:

Synaptophysin 1

WT:

Wild-type

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Acknowledgements

The work described in this paper has been supported by local grants of the University of Turin. CC is in receipt of a grant of the Italian Ministry of Education and Research (MIUR).

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Authors and Affiliations

  1. Department of Veterinary Sciences, University of Turin, Largo Paolo Braccini 2, I-10095, Turin, Grugliasco (TO), Italy

    Claudia Castagna, Adalberto Merighi & Laura Lossi

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  1. Claudia Castagna
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  2. Adalberto Merighi
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  3. Laura Lossi
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Contributions

CC collected animal samples, processed them for immunocytochemistry, acquired and processed IMF images, collaborated to statistical analysis, and has been involved in drafting the manuscript and interpretation of data. AM substantially contributed to the conception and design of the experiments, performed statistical analysis, interpreted data, and wrote the manuscript. LL made substantial contributions to the conception and design of the study, collaborated to the acquisition of digital images and the interpretation of data, and critically revised the initial manuscript draft. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.

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Correspondence to Claudia Castagna.

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The experiments described in this paper were approved by the Animal Welfare Committee of the Department of Veterinary Sciences of the University of Turin and by the Italian Ministry of Health (authorization n° 65/2016-PR).

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Castagna, C., Merighi, A. & Lossi, L. Decreased Expression of Synaptophysin 1 (SYP1 Major Synaptic Vesicle Protein p38) and Contactin 6 (CNTN6/NB3) in the Cerebellar Vermis of reln Haplodeficient Mice. Cell Mol Neurobiol 39, 833–856 (2019). https://doi.org/10.1007/s10571-019-00683-7

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