ORCID Profile
0000-0002-0226-7855
Current Organisation
The University of Edinburgh
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Publisher: Cold Spring Harbor Laboratory
Date: 27-12-2021
DOI: 10.1101/2021.12.21.473638
Abstract: Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence occur in many disorders 1–10 , suggesting that brain circuits possess an intrinsic capacity to repair themselves. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6 , a neurodevelopmental disorder model 11 . Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the postnatal expansion of synapse ersity and acquisition of normal synaptome architecture were delayed in all brain regions, interfering with network and cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synaptome architecture to its normal developmental trajectory. Synapse subtypes with high rates of protein turnover mediated these events. These results show synaptome remodelling confers resilience to neurodevelopmental disorders.
Publisher: Springer Science and Business Media LLC
Date: 11-11-2022
DOI: 10.1038/S41467-022-34131-W
Abstract: Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Nevertheless, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence can occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome the deficits arising from some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6 , a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse ersity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with networks and electrophysiological simulations of cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synapse ersity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders.
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.NEURON.2022.09.009
Abstract: The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous PSD95, an abundant postsynaptic protein in excitatory synapses, at single-synapse resolution across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of PSD95 lifetimes extending from hours to several months, with distinct spatial distributions in dendrites, neurons, and brain regions. Synapses with short protein lifetimes are enriched in young animals and in brain regions controlling innate behaviors, whereas synapses with long protein lifetimes accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. Synapse protein lifetime increases throughout the brain in a mouse model of autism and schizophrenia. Protein lifetime adds a further layer to synapse ersity and enriches prevailing concepts in brain development, aging, and disease.
Publisher: Cold Spring Harbor Laboratory
Date: 12-11-2019
DOI: 10.1101/838458
Abstract: How synapses change molecularly during the lifespan and across all brain circuits is unknown. We analyzed the protein composition of billions of in idual synapses from birth to old age on a brain-wide scale in the mouse, revealing a program of changes in the lifespan synaptome architecture spanning in idual dendrites to the systems level. Three major phases were uncovered, corresponding to human childhood, adulthood and old age. An arching trajectory of synaptome architecture drives the differentiation and specialization of brain regions to a peak in young adults before dedifferentiation returns the brain to a juvenile state. This trajectory underscores changing network organization and hippoc al physiology that may account for lifespan transitions in intellectual ability and memory, and the onset of behavioral disorders. The synaptome architecture of the mouse brain undergoes continuous changes that organize brain circuitry across the lifespan.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-07-2020
Abstract: Excitatory synapses connect neurons in the brain to build the circuits that enable behavior. Cizeron et al. surveyed synapses in the mouse brain from birth to old age and present the data as a community resource, the Mouse Lifespan Synaptome Atlas (see the Perspective by Micheva et al. ). Molecular and morphological features defined 37 subtypes of synapses. Although synapse density generally increased in early development and declined in old age, the details differed in different brain areas. Science this issue p. 270 see also p. 253
Publisher: Elsevier BV
Date: 08-2018
Publisher: Cold Spring Harbor Laboratory
Date: 17-12-2021
DOI: 10.1101/2021.12.16.472938
Abstract: Protein turnover is required for synapse maintenance and remodelling and may impact memory duration. We quantified the lifetime of postsynaptic protein PSD95 in in idual excitatory synapses across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of protein lifetimes that may extend from a few hours to several months, with distinct spatial distributions in dendrites, neuron types and brain regions. Short protein lifetime (SPL) synapses are enriched in developing animals and in regions controlling innate behaviors, whereas long protein lifetime (LPL) synapses accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. The protein lifetime synaptome architecture is disrupted in an autism model, with synapse protein lifetime increased throughout the brain. These findings add a further layer to synapse ersity in the brain and enrich prevailing concepts in behavior, development, ageing and brain repair.
Publisher: Cold Spring Harbor Laboratory
Date: 19-07-2023
DOI: 10.1101/2023.07.19.549645
Abstract: How sleep deprivation affects cognition remains elusive. Synaptome mapping of excitatory synapses in 125 regions of the mouse brain revealed that sleep deprivation selectively reduces synapse ersity in the cortex and hippoc us. Sleep deprivation targeted specific types and subtypes of excitatory synapses while maintaining total synapse density. Altered synaptic responses to neural oscillations in a computational model suggest that sleep prevents cognitive impairments by maintaining normal brain synaptome architecture.
Publisher: Wiley
Date: 25-06-2020
DOI: 10.1111/EJN.14846
Abstract: Mapping the molecular composition of in idual excitatory synapses across the mouse brain reveals high synapse ersity with each brain region showing a distinct composition of synapse types. As a first step towards systematic mapping of synapse ersity across the human brain, we have labelled and imaged synapses expressing the excitatory synapse protein PSD95 in twenty human brain regions, including 13 neocortical, two subcortical, one hippoc al, one cerebellar and three brainstem regions, in four phenotypically normal in iduals. We quantified the number, size and intensity of in idual synaptic puncta and compared their regional distributions. We found that each region showed a distinct signature of synaptic puncta parameters. Comparison of brain regions showed that cortical and hippoc al structures are similar, and distinct from those of cerebellum and brainstem. Comparison of synapse parameters from human and mouse brain revealed conservation of parameters, hierarchical organization of brain regions and network architecture. This work illustrates the feasibility of generating a systematic single‐synapse resolution atlas of the human brain, a potentially significant resource in studies of brain health and disease.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
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