title: Single-synapse resolution molecular mapping reveals both widespread and highly targeted experience-dependent synaptic plasticity in the mammalian brain
Creators: name: Woods, Hanan
Publisher: name: The University of Edinburgh
Year: 2024
Subjects: subject: experience-dependent plasticity
subject: synapse
subject: synaptome
subject: PSD-95
subject: SAP-102

description: Systematic mapping of the molecular, morphological and protein half-life properties of individual excitatory synapses on a brain-wide scale in the mouse has revealed high synapse diversity. Excitatory synapse diversity expands during postnatal development and each brain region develops a unique signature of synapse composition (Bulovaite et al., 2022; Cizeron et al., 2020; Zhu et al., 2018). These findings have given rise to the terms ‘synaptome’, which describes the full diversity of brain synapses, and ‘the synaptome architecture’, which describes the spatial distribution of these synapses in neurons, brain regions and the whole brain. Genetic mutations cause widespread changes in synaptome architecture, indicating that it is genetically pro grammed (Bulovaite et al., 2022; Tomas-Roca et al., 2022; Zhu et al., 2018). The extent to which daily activity and experience shape the synaptome architecture is poorly understood, with large parts of the brain remaining unexplored. We asked whether the development of synaptome architecture was modified in two well-established, complementary paradigms used to study how experience modifies synaptic properties: environmental enrichment (EE), which stimulates many sensory inputs; and monocular deprivation (MD), which specifically alters visual inputs. Psd95eGFP/eGFP;Sap102MKO2/MKO2 mice expressing fluorescently labelled post-synaptic proteins underwent MD from P26-31 ([MD n = 13 (6F); control n = 14 (7F)]) or EE rearing until P90 ([EE n = 23 (12F); control (standard-caged) n = 29 (15F)]) and synaptome mapping was performed at single-synapse resolution on a brain-wide scale. Both MD and EE modified the synaptome architecture in many brain regions and beyond the areas typically explored in the literature. Specific excitatory synapse types and subtypes, as dictated by their protein composition and protein lifetime, were targeted among the experience-dependent changes. For example, whereas 3- month EE rearing until adulthood resulted in a lower density of long-lifetime PSD-95+ synapses across the isocortex, 6-day juvenile MD produced a higher density of shorter-lifetime PSD-95+/ SAP-102+ synapses in these same brain regions in both hemispheres relative to controls. Both paradigms stimulated a trend of lower long-protein lifetime synapse abundance relative to short-protein lifetime synapses, which contrasted with the effects of sleep-deprivation on synaptome architecture. In addition, EE- and MD-induced experience-dependent plasticity of synaptome architecture showed both similarities and differences between female and male mice, high-lighting sex-dependent modifications of synapse populations with experience. That experience plays a role in modulating particular subtypes of synapses in the developing mammalian brain has key implications for existing models of learning and synapse pathology sensitive to envi ronmental factors.
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