Enhanced synapse remodelling as a common phenotype in mouse models of autism

Abstract

Developmental deficits in neuronal connectivity are considered to be present in patients with autism spectrum disorders (ASDs). Here we examine this possibility by using in vivo spine imaging in the early postnatal cortex of ASD mouse models. Spines are classified by the presence of either the excitatory postsynaptic marker PSD-95 or the inhibitory postsynaptic marker gephyrin. ASD mouse models show consistent upregulation in the dynamics of PSD-95-positive spines, which may subsequently contribute to stable synaptic connectivity. In contrast, spines receiving inputs from the thalamus, detected by the presence of gephyrin clusters, are larger, highly stable and unaffected in ASD mouse models. Importantly, two distinct mouse models, human 15q11-13 duplication and neuroligin-3 R451C point mutation, show highly similar phenotypes in spine dynamics. This selective impairment in dynamics of PSD-95-positive spines receiving intracortical projections may be a core component of early pathological changes and be a potential target of early intervention.

Autism spectrum disorder: neuropathology and animal models

“…Nlgn3 R451C knock-in (KI) mice, that express the Nlgn3 R451C mutation found in individuals with ASD [174], also show reduction in volume of the hippocampus, striatum, thalamus, cerebral peduncle, corpus callosum, fimbria/fornix and internal capsule [97]. Synaptic changes in the Nlgn3 KI mice include greater postnatal turnover of excitatory spines in layer II and III pyramidal neurons in the anterior frontal cortex [172], and increased vesicular GABA transporter expression without changes in inhibitory synapse number or ultrastructure in neurons in the somatosensory cortex [345]. In the hippocampus, increased dendritic complexity in the stratum radiatum, unaltered spine density or postsynaptic density (PSD) length, as well as decreased presynaptic bouton size, vesicle numbers and spine area are observed in Nlgn3 KI mice [99].…”

“…However, reduced volume was detected by MRI in the stratum granulosum of the hippocampus, the inferior and superior colliculi, the hypothalamus, the thalamus, the pons and the midbrain of patDp /+ mice [98]. PatDp /+ mice, but not matDp /+ mice, show increased postnatal turnover of excitatory spines in the somatosensory and anterior frontal cortex [172]. Further investigation of neuronal development and migration in these mouse models will reveal the role played by this chromosomal region in ASD.…”

Abnormal instability, excess density, and aberrant morphology of dendritic spines in prenatally testosterone-exposed mice

“…These lines of evidence are consistent with our present study that demonstrated excess density of spines in prenatally testosterone-exposed mice. It should be noted that the above genetic models of neurodevelopmental disorders associated with autistic syndrome have not demonstrated increased spine density (Cruz-Martin et al, 2010;Isshiki et al, 2014;Jiang et al, 2013;Pan et al, 2010). Prenatally testosterone-exposed mice reproduced both features of ASD synaptic pathology: synaptic instability and excess spines.…”

“…Other studies using genetic animal models of neurodevelopmental disorders associated with autistic syndrome have also demonstrated abnormal dynamics of the synapse. Genetic mouse models of ASD, human 15q11-13 duplication and neuroligin-3 R451C mutation, exhibit increased instability of PSD-95-positive dendritic spines (Isshiki et al, 2014). A mouse model of fragile X syndrome, FMR1 knock-out mice, shows synaptic instability and insensitivity to sensory experience (Cruz-Martin et al, 2010;Pan et al, 2010).…”

Integrative Approach to Child and Adolescent Mental Health

“…Understanding the symptoms and course of action for each individual, as well as the biology ranging from genetic and environmental risk factors to the neural circuits involved, remains a substantial challenge for geneticists and neurobiologists [27][28][29]. Many mechanisms of human brain development remain hidden, but neuroscientists are beginning to uncover some of these complex steps through extensive studies [30][31][32]. Research inds that neurons migrate from their birthplace near the ventricular walls to their inal destination in the brain.…”