Biology subjects

Komiyama, N.

Publications and source records attributed to Komiyama, N..

9 recordsLinked to original sources

bioRxiv2026

A Brainwide Atlas of Synaptic Nanoarchitecture Across the Mouse Lifespan

How biological complexity emerges from the ordered assembly of molecular building blocks into supramolecular systems remains a central question, particularly in the mammalian brain with its vast synaptic diversity. We introduce NanoSYNMAP, a genetic, optical, and computational platform that integrates FRET with synaptome mapping to quantify nanoscale proximity of proteins in individual synapses brain-wide. We generate the first brain atlas of synaptic nanoarchitecture, based on the proximity of postsynaptic MAGUK supercomplexes. This reveals a molecular logic in which spacing of supramolecular assemblies specifies nanoscale architecture that organizes the global synaptome architecture. Nanoarchitecture varies across brain regions, differentiates during postnatal development, and remodels with aging. Supercomplex proximity reflects scaffold abundance, nanodomain organization, and competitive interactions among MAGUK assemblies. Deletion of a neuropsychiatric risk gene triggers widespread reorganization of nanoscale architecture. These findings establish molecular proximity as a fundamental scalable dimension of synapse diversity in health and disease.

neuroscience↗

bioRxiv2025

Experiences are encoded by brainwide reprogramming of synaptome architecture

Synaptome architecture describes the spatiotemporal distribution of highly diverse excitatory synapses throughout the brain. Whether and how this architecture is impacted by experience is key to understanding its role in learning and memory. We found that environmental enrichment and monocular visual deprivation drive large-scale, type-and subtype-specific reorganisation of excitatory synapses in more than one hundred brain regions. Each experience modifies distinct subsets of synapses, with patterns aligned with protein turnover rates and connectome architecture. These reorganisations occur during development and adulthood, revealing a conserved mechanism of synaptome plasticity across the lifespan. Our findings support a population-selection model in which experience drives adaptation by selectively modifying synapse varieties, generating a distributed trace of past experiences. Our results also point to synaptome architecture as a shared framework integrating experience, lifespan changes, sleep, genetic variation and disease.

neuroscience↗

bioRxiv2025

Developmental plasticity facilitates the structural maturation of cochlear inner hair cell ribbon synapses

Sound detection occurs in the cochlea, where sensory inner hair cells (IHC) accurately convert auditory stimuli into neurochemical signals. Presynaptically, IHCs harbor synaptic ribbons, specialized scaffolds that facilitate ultrafast and indefatigable exocytosis. During synapse assembly and subsequent maturation, IHC ribbons increase in volume and synaptic vesicle tethering capacity. This development is thought to result from progressive precursor aggregation. However, the underlying mechanisms of ribbon synapse formation have remained elusive thus far. In this study, we established a novel triple-color live-cell imaging approach to monitor IHC pre-synaptogenesis in situ. We found that ribbon precursors are highly dynamic and undergo bidirectional plasticity. The presynaptic active zone (AZ) forms a focal point for dramatic structural remodeling of precursors, which the AZ recruits, confines and redistributes. Furthermore, silencing spontaneous synaptic activity decreased precursor mobility and plasticity at the AZ. This suggests a fundamental role for activity-dependent Ca2+ influx in the plastic development shaping the unique properties of auditory ribbon synapses.

neuroscience↗

bioRxiv2024

Non-ionotropic signaling through the NMDA receptor GluN2B carboxy terminal domain drives morphological plasticity of dendritic spines and reverses fragile X phenotypes in mouse hippocampus

It is well known that activation of NMDA receptors can trigger long-term synaptic depression (LTD) and that a morphological correlate of this functional plasticity is spine retraction and elimination. Recent studies have led to the surprising conclusion that NMDA-induced spine shrinkage proceeds independently of ion flux and requires the initiation of de novo protein synthesis, highlighting an unappreciated contribution of mRNA translation to non-ionotropic NMDAR signaling. Here we used NMDA-induced spine shrinkage in slices of mouse hippocampus as a readout to investigate this novel modality of synaptic transmission. By using selective pharmacological and genetic tools, we find that structural plasticity is dependent on the ligand binding domain (LBD) of GluN2B-containing NMDA receptors and that metabotropic signaling occurs via the GluN2B carboxyterminal domain (CTD). Disruption of signaling by replacing the GluN2B CTD with the GluN2A CTD leads to increased spine density, dysregulated basal protein synthesis, and epileptiform activity in area CA3 reminiscent of phenotypes observed in the Fmr1-/y model of fragile X syndrome. By crossing the Fmr1-/y mice with animals in which the GluN2A CTD has been replaced with the GluN2B CTD, we observe a correction of these core fragile X phenotypes. These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for treatment of fragile X and related causes of intellectual disability and autism.

neuroscience↗

bioRxiv2023

Sleep maintains excitatory synapse diversity in the cortex and hippocampus

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 diversity in the cortex and hippocampus. 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.

neuroscience↗

bioRxiv2023

The organisation and turnover of synaptic proteins within molecular supercomplexes.

The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Cricks 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP and mEos2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Cricks model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored.

neuroscience↗

bioRxiv2021

Developmental resilience of synaptome architecture

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 disorders1-10, 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 model11. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the postnatal expansion of synapse diversity 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.

neuroscience↗

bioRxiv2021

A brain atlas of synapse protein lifetime across the mouse lifespan.

Protein turnover is required for synapse maintenance and remodelling and may impact memory duration. We quantified the lifetime of postsynaptic protein PSD95 in individual 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 diversity in the brain and enrich prevailing concepts in behavior, development, ageing and brain repair.

neuroscience↗

bioRxiv2019

A lifespan program of mouse synaptome architecture

How synapses change molecularly during the lifespan and across all brain circuits is unknown. We analyzed the protein composition of billions of individual 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 individual 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 hippocampal physiology that may account for lifespan transitions in intellectual ability and memory, and the onset of behavioral disorders. One sentence summaryThe synaptome architecture of the mouse brain undergoes continuous changes that organize brain circuitry across the lifespan.

neuroscience↗