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Identification of the common neurobiological process disturbed in genetic and non-genetic models for autism spectrum disorders

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Abstract

Autism spectrum disorders (ASD) are neurodevelopmental disorders. Genetic factors, along with non-genetic triggers, have been shown to play a causative role. Despite the various causes, a triad of common symptoms defines individuals with ASD; pervasive social impairments, impaired social communication, and repeated sensory-motor behaviors. Therefore, it can be hypothesized that different genetic and environmental factors converge on a single hypothetical neurobiological process that determines these behaviors. However, the cellular and subcellular signature of this process is, so far, not well understood. Here, we performed a comparative study using “omics” approaches to identify altered proteins and, thereby, biological processes affected in ASD. In this study, we mined publicly available repositories for genetic mouse model data sets, identifying six that were suitable, and compared them with in-house derived proteomics data from prenatal zinc (Zn)-deficient mice, a non-genetic mouse model with ASD-like behavior. Findings derived from these comparisons were further validated using in vitro neuronal cell culture models for ASD. We could show that a protein network, centered on VAMP2, STX1A, RAB3A, CPLX2, and AKAP5, is a key convergence point mediating synaptic vesicle release and recycling, a process affected across all analyzed models. Moreover, we demonstrated that Zn availability has predictable functional effects on synaptic vesicle release in line with the alteration of proteins in this network. In addition, drugs that target kinases, reported to regulate key proteins in this network, similarly impacted the proteins’ levels and distribution. We conclude that altered synaptic stability and plasticity through abnormal synaptic vesicle dynamics and function may be the common neurobiological denominator of the shared behavioral abnormalities in ASD and, therefore, a prime drug target for developing therapeutic strategies.

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Data availability

The data sets and analysis pipelines generated for this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The Autism Research Institute funds AMG. The authors would like to acknowledge networking support by the COST Action TD1304. SM and SEH are funded by the Irish Research Council (IRC) postgraduate grants; GOIPG/2019/3693 and ESPG/2020/88, respectively.

Funding

The Autism Research Institute funds AMG. SM and SEH are funded by the Irish Research Council (IRC) postgraduate grants; GOIPG/2019/3693 and ESPG/2020/88, respectively.

Author information

Author notes

  1. Sigita Malijauskaite, Ann Katrin Sauer, Andreas M. Grabrucker and Kieran McGourty contributed equally to the work.

Authors and Affiliations

  1. Bernal Institute, University of Limerick, Analog Devices Building AD3-018, AD3-019, Castletroy, Limerick, V94PH61, Ireland

    Sigita Malijauskaite, Ann Katrin Sauer, Seamus E. Hickey, Marco Franzoni, Andreas M. Grabrucker & Kieran McGourty

  2. Department of Chemical Sciences, University of Limerick, Limerick, Ireland

    Sigita Malijauskaite, Seamus E. Hickey, Marco Franzoni & Kieran McGourty

  3. Cellular Neurobiology and Neuro-Nanotechnology Lab, Department of Biological Sciences, University of Limerick, Limerick, Ireland

    Ann Katrin Sauer & Andreas M. Grabrucker

  4. Health Research Institute (HRI), University of Limerick, Limerick, Ireland

    Ann Katrin Sauer, Andreas M. Grabrucker & Kieran McGourty

  5. Synthesis and Solid State Pharmaceutical Centre, University of Limerick, Limerick, Ireland

    Kieran McGourty

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Contributions

SM, AKS, AMG, and KMcG contributed to the study conception and design. Material preparation, data collection, and analysis were performed by SM, AKS, MF, AMG, and KMcG. AMG and KMcG wrote the first draft of the manuscript, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Andreas M. Grabrucker or Kieran McGourty.

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Conflict of interest

SM, AKS, SEH, MF, AMG, and KMcG declare that there is no conflict of interest regarding the publication of this paper.

Ethical approval

Animal experiments were performed in compliance with guidelines from the Federal Government of Germany for the welfare of experimental animals and approved by the Regierungspräsidium Tübingen and the local ethics committee (Ulm-University) ID:Number:1239 during AMG’s previous appointment at Ulm University.

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Supplementary Information

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18_2022_4617_MOESM1_ESM.tif

Supplementary file1 Immunoblot quantification of AKAP5 A AKAP5 protein immunoblot analysis using Control and PZD mouse hippocampal brain lysates. Data are normalized to the housekeeping protein ACTIN and shown as mean ± SEM. A significantly higher AKAP5 protein expression was found in PZD brain lysates (t test; p ≤ 0.001). B Exemplary WB bands. (TIF 17729 KB)

18_2022_4617_MOESM2_ESM.tif

Supplementary file2 Detection and quantification of neuronal synapses and pre-synaptic assemblies Rat hippocampal neurons were grown either in full growth media (CTL) for 14 DIV or changed into growth media additionally supplemented with 50 µM CaEDTA for 14 DIV (CaEDTA) prior to measurement by fluorescent microscopy and downstream image analysis. A (i) Microscopy image quantification of the median number of synapses (marked by co-localizing homer and synaptophysin punctae) or pre-synaptic assemblies (marked by AKAP5 and SNAP25 punctae) per neuronal cell in CaEDTA conditions normalized to control conditions. (ii) Microscopy image quantification of the median number of punctae of homer, synatophysin, AKAP5 or SNAP25 per neuronal cell in CaEDTA conditions normalized to control conditions. B Proportional fluorescence intensity density plot analysis in synapses (Homer&Synatophysin) and pre-synaptic assemblies (AKAP5&SNAP25) in neurons cultured under control conditions or supplemented with CaEDTA C) Quantification of indicated proteins through fluorescence intensity analysis in synapses (Homer&Synatophysin) and pre-synaptic assemblies (AKAP5&SNAP25) in neurons cultured in control or CaEDTA conditions. A minimum of 80,000 synapse/pre-synaptic assemblies per condition per experiment were detected in control conditions and a minimum of 50,000 in CaEDTA conditions. Data were aggregated across experimental repeats (n = 3) and represent the geometric mean of each marker within a synapse (Homer&Synatophysin) /pre-synaptic (AKAP5&SNAP25) assembly identified through image analysis. Data were analysed by student’s t tests comparisons of two independent groups: *P<0.05; **P<0.01; ***P<0.001; n.s. not significant (TIF 54577 KB)

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Malijauskaite, S., Sauer, A.K., Hickey, S.E. et al. Identification of the common neurobiological process disturbed in genetic and non-genetic models for autism spectrum disorders. Cell. Mol. Life Sci. 79, 589 (2022). https://doi.org/10.1007/s00018-022-04617-3

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