Abstract
Background: Altered synaptic number, structure and function are thought to be key neurobiological mechanisms underpinning many autistic features, as suggested by genetic (Bourgeron, 2015), post-mortem (Nicolini et al., 2015) and animal model (Tang et al., 2014) research. However, there is limited in vivo evidence about whether synaptic density is altered in autistic people.
Objectives: We conducted the first multi-site, translational study of synaptic density in autistic people and in ‘idiopathic’ and ‘monogenic’ mouse models of autism, using positron emission tomography (PET) and autoradiography, respectively. We hypothesised 1) that synaptic density would be altered in autistic compared to non-autistic adults in fronto-temporal regions (Hutsler & Zhang, 2010; Nakamura et al., 2011; Nicolini et al., 2015), the amygdala (Schumann & Amaral, 2006), the basal ganglia and the cerebellum (Wegiel et al., 2014), and 2) altered profiles of synaptic density differences (compared to wildtypes) in idiopathic versus monogenic mouse models.
Methods: Across three study sites, we included 30 autistic adults (22 males, aged 19–58), and 52 non-autistic controls (42 male) who did not differ on full-scale IQ. No participants had co-occurring physical or developmental conditions. In vivo synaptic density was estimated using the radioligand 11C-UCB-J, which binds to the pre-synaptic protein SV2A. Our primary metric was the non-displaceable binding-potential (BPND) of 11C-UCB-J, where centrum semiovale was used as reference region. Analyses were replicated using the distribution volume (Vt) of 11C-UCB-J. Autistic traits were quantified using the Social Responsiveness Scale-II.
We performed 3H-UCB-J autoradiography to quantify synaptic density in the BTBR T+tf/J idiopathic autism mouse model (with strong face validity, but unknown genetics), two monogenic mouse models with mutations in synaptic genes linked with autism in humans: Nlgn3R451C knock-in and Nrxn1α knock-out mice, and wildtype controls specific to each model.
Results: Across hypothesised regions, 11C-UCB-J BPND was significantly lower (by 5.8 %) in autistic compared to non-autistic people. In region-specific analyses, 11C-UCB-J BPND was significantly lower in autistic people in the anterior cingulate cortex, the temporal cortex, the nucleus accumbens, amygdala and cerebellum. Greater autistic traits across groups correlated with lower 11C-UCB-J BPND. Consistent results were obtained using 11C-UCB-J Vt.
In the BTBR mouse model, 3H-UCB-J was lower in the sensory and auditory cortices, the striatum, hippocampus, amygdala, thalamus and hypothalamus, compared to C57Bl6/J wildtypes (Figure 1). In the Nlgn3R451C knock-in model, 3H-UCB-J was decreased in the hypothalamus but increased in the amygdala compared to wildtype littermates. There were no significant differences in 3H-UCB-J between Nrxn1α knock-out mice and their wildtype controls.
Conclusions: We report findings from the largest in vivo study of synaptic density in autistic people. Converging evidence from autistic adults and the BTBR mouse model highlights a significant reduction in synaptic density in ‘idiopathic’ autism. Implicated brain regions are known to be associated with autistic behaviours. Further, we provide convergent biological validity for BTBR mice as an animal model for pre-synaptic density in idiopathic autism, enabling back-translation.
Objectives: We conducted the first multi-site, translational study of synaptic density in autistic people and in ‘idiopathic’ and ‘monogenic’ mouse models of autism, using positron emission tomography (PET) and autoradiography, respectively. We hypothesised 1) that synaptic density would be altered in autistic compared to non-autistic adults in fronto-temporal regions (Hutsler & Zhang, 2010; Nakamura et al., 2011; Nicolini et al., 2015), the amygdala (Schumann & Amaral, 2006), the basal ganglia and the cerebellum (Wegiel et al., 2014), and 2) altered profiles of synaptic density differences (compared to wildtypes) in idiopathic versus monogenic mouse models.
Methods: Across three study sites, we included 30 autistic adults (22 males, aged 19–58), and 52 non-autistic controls (42 male) who did not differ on full-scale IQ. No participants had co-occurring physical or developmental conditions. In vivo synaptic density was estimated using the radioligand 11C-UCB-J, which binds to the pre-synaptic protein SV2A. Our primary metric was the non-displaceable binding-potential (BPND) of 11C-UCB-J, where centrum semiovale was used as reference region. Analyses were replicated using the distribution volume (Vt) of 11C-UCB-J. Autistic traits were quantified using the Social Responsiveness Scale-II.
We performed 3H-UCB-J autoradiography to quantify synaptic density in the BTBR T+tf/J idiopathic autism mouse model (with strong face validity, but unknown genetics), two monogenic mouse models with mutations in synaptic genes linked with autism in humans: Nlgn3R451C knock-in and Nrxn1α knock-out mice, and wildtype controls specific to each model.
Results: Across hypothesised regions, 11C-UCB-J BPND was significantly lower (by 5.8 %) in autistic compared to non-autistic people. In region-specific analyses, 11C-UCB-J BPND was significantly lower in autistic people in the anterior cingulate cortex, the temporal cortex, the nucleus accumbens, amygdala and cerebellum. Greater autistic traits across groups correlated with lower 11C-UCB-J BPND. Consistent results were obtained using 11C-UCB-J Vt.
In the BTBR mouse model, 3H-UCB-J was lower in the sensory and auditory cortices, the striatum, hippocampus, amygdala, thalamus and hypothalamus, compared to C57Bl6/J wildtypes (Figure 1). In the Nlgn3R451C knock-in model, 3H-UCB-J was decreased in the hypothalamus but increased in the amygdala compared to wildtype littermates. There were no significant differences in 3H-UCB-J between Nrxn1α knock-out mice and their wildtype controls.
Conclusions: We report findings from the largest in vivo study of synaptic density in autistic people. Converging evidence from autistic adults and the BTBR mouse model highlights a significant reduction in synaptic density in ‘idiopathic’ autism. Implicated brain regions are known to be associated with autistic behaviours. Further, we provide convergent biological validity for BTBR mice as an animal model for pre-synaptic density in idiopathic autism, enabling back-translation.
| Original language | English |
|---|---|
| Title of host publication | Developmental Medicine & Child Neurology |
| Pages | S7-S18 |
| Number of pages | 1 |
| Volume | 68 |
| DOIs | |
| Publication status | E-pub ahead of print - 26 Jan 2026 |
Publication series
| Name | Developmental medicine and child neurology |
|---|
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