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

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.

Rare heterozygous genetic variants of NRXN and NLGN gene families involved in synaptic function and their association with neurodevelopmental disorders

“…No self-care skills had been acquired. In previous reports, aggression, hyperactivity, and sleep problems were marked for deletions of the NRXN1 gene in human studies, not in animal studies (Chawner et al, 2019;Molloy et al, 2023).…”

“…In this study, the 2p16.3 deletion was detected in two different individuals. To date, mono/biallelic CNVs in NRXN genes have been mainly associated with incomplete penetrance and pleiotropy, DD, and neuropsychiatric disorders such as ASD (Dabell et al, 2013;Gerik-Celebi et al, 2023;Molloy et al, 2023). Homozygous deletion of the 2p16.3 region, including the NRXN1 gene, has been better identified.…”

“…Reported variants associated with the NLGN gene family and neurodevelopmental disorders are less common. However, it maintains its importance in neurodevelopmental disorders because it is an important part of early neurodevelopment (Molloy et al, 2023). In particular, variants in the NLGN3 and NLGN4X genes have been reported as leading impairments in synaptogenesis for neurodevelopmental disorders (Molloy et al, 2023;Nguyen et al, 2020).…”

“…In contrast, NLGN2 is localized at inhibitory or GABAergic synapses (Bemben et al, 2019;Chubykin et al, 2007). NLGN3 is involved in both synapse subtypes, especially in excitatory synapses (Molloy et al, 2023). NLGN4 is present at inhibitory glycinergic synapses (Marro et al, 2010).…”

Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction

“…SHANK3 is recognized to be strongly associated to ASD in large population studies and is the primary genetic driver of the neurodevelopmental disability seen in Phelan McDermid syndrome ( 83 ). Pre-clinical models of Shank3 disruption have demonstrated similar behavioral and neurological phenotypic traits, including abnormal socialization, repetitive behaviors, and other motoric alterations ( 52 , 84 ). Other potential associations under investigation include a non-physiological decline in SHANK3 expression leading to degeneration of excitatory synapses as part of the pathogenesis of Alzheimer’s disease ( 85 ).…”