Bridging the translational gap: what can synaptopathies tell us about autism?

Ciara J Molloy; Jennifer Cooke; Nicholas J F Gatford; Alejandro Rivera-Olvera; Sahar Avazzadeh; Judith R Homberg; Joanes Grandjean; Cathy Fernandes; Sanbing Shen; Eva Loth; Deepak P Srivastava; Louise Gallagher

doi:10.3389/fnmol.2023.1191323

Bridging the translational gap: what can synaptopathies tell us about autism?

Front Mol Neurosci. 2023 Jun 27:16:1191323. doi: 10.3389/fnmol.2023.1191323. eCollection 2023.

Authors

Ciara J Molloy¹, Jennifer Cooke², Nicholas J F Gatford³, Alejandro Rivera-Olvera⁴, Sahar Avazzadeh⁵, Judith R Homberg⁴, Joanes Grandjean^{5

6}, Cathy Fernandes^{7

8}, Sanbing Shen^{9

10}, Eva Loth², Deepak P Srivastava^{8

11}, Louise Gallagher^{1

12

13

14

15}

Affiliations

¹ Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.
² Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
³ Kavli Institute for Nanoscience Discovery, Nuffield Department of Clinical Neurosciences, University of Oxford, Medical Sciences Division, Oxford, United Kingdom.
⁴ Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands.
⁵ Physiology and Cellular Physiology Research Laboratory, CÚRAM SFI Centre for Research in Medical Devices, School of Medicine, Human Biology Building, University of Galway, Galway, Ireland.
⁶ Department of Medical Imaging, Radboud University Medical Centre, Nijmegen, Netherlands.
⁷ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁸ MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁹ Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland.
¹⁰ FutureNeuro, The SFI Research Centre for Chronic and Rare Neurological Diseases, Royal College of Surgeons, Dublin, Ireland.
¹¹ Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
¹² The Hospital for SickKids, Toronto, ON, Canada.
¹³ The Peter Gilgan Centre for Research and Learning, SickKids Research Institute, Toronto, ON, Canada.
¹⁴ The Centre for Addiction and Mental Health, Toronto, ON, Canada.
¹⁵ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Abstract

Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism and other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved in synaptic biology. Synaptopathies are commonly associated with autism and developmental delay and may be associated with a range of other neuropsychiatric outcomes. Altered synaptic biology is suggested by both preclinical and clinical studies in autism based on evidence of differences in early brain structural development and altered glutamatergic and GABAergic neurotransmission potentially perturbing excitatory and inhibitory balance. This review focusses on the NRXN-NLGN-SHANK pathway, which is implicated in the synaptic assembly, trans-synaptic signalling, and synaptic functioning. We provide an overview of the insights from preclinical molecular studies of the pathway. Concentrating on NRXN1 deletion and SHANK3 mutations, we discuss emerging understanding of cellular processes and electrophysiology from induced pluripotent stem cells (iPSC) models derived from individuals with synaptopathies, neuroimaging and behavioural findings in animal models of Nrxn1 and Shank3 synaptic gene conditions, and key findings regarding autism features, brain and behavioural phenotypes from human clinical studies of synaptopathies. The identification of molecular-based biomarkers from preclinical models aims to advance the development of targeted therapeutic treatments. However, it remains challenging to translate preclinical animal models and iPSC studies to interpret human brain development and autism features. We discuss the existing challenges in preclinical and clinical synaptopathy research, and potential solutions to align methodologies across preclinical and clinical research. Bridging the translational gap between preclinical and clinical studies will be necessary to understand biological mechanisms, to identify targeted therapies, and ultimately to progress towards personalised approaches for complex neurodevelopmental conditions such as autism.

Keywords: NRXN1 deletion; Phelan-McDermid syndrome; SHANK3; animal models; autism; induced pluriopotent stem cells; preclinical models; synaptopathy.

Publication types

Review