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.

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

Figure 1

Overview of brain and behavioural phenotypes reported in clinical and preclinical model research studies of NRXN1/Nrxn1 deletion (Blue) and PMD/Shank3 (Green) to date. Noteworthy, many of the findings shown are based on single studies, therefore should be interpreted as preliminary findings, with future replication needed. Created with BioRender.com. ADHD, attention deficit hyperactivity disorder; AEP, auditory evoked potential; Am, amygdala; BG, basal ganglia; Ca2+, calcium; CC, corpus callosum; Cer, cerebellum; Cor, cortex; Ent, entorhinal; Glu, glutamate; Hipp, hippocampus; ID, intellectual disability; IFOF, inferior fronto-occipital fasciculus; Occ, occipital; OCD, obsessive compulsive disorder; PFC, prefrontal cortex; SCZ, schizophrenia; STG, superior temporal gyrus, Str, striatum; Tha, thalamus; UF, uncinate fasiculus; USV, ultrasonic vocalisations; VEP, visual evoked potential; WM, white matter.