Molecular organization of central cholinergic synapses DOI Creative Commons
Justin Rosenthal,

Dean Zhang,

Jun Yin

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(17)

Published: April 24, 2025

Synapses have undergone significant diversification and adaptation, contributing to the complexity of central nervous system. Understanding their molecular architecture is essential for deciphering brain’s functional evolution. While nicotinic acetylcholine receptors (nAchRs) are widely distributed across metazoan brains, associated protein networks remain poorly characterized. Using in vivo proximity labeling, we generated proteomic maps subunit-specific nAchR interactomes developing mature Drosophila brains. Our findings reveal a developmental expansion reconfiguration interactome. Proteome profiling with genetic perturbations showed that removing individual subunits consistently triggers compensatory shifts receptor subtypes, highlighting mechanisms synaptic plasticity. We also identified Rho-GTPase regulator Still life (Sif) as key organizer cholinergic synapses, loss Sif disrupting composition structural integrity. These results provide insights into development plasticity advancing our understanding identity conservation divergence.

Language: Английский

Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology DOI Creative Commons
Prateek Kumar, Annie M Goettemoeller, Claudia Espinosa‐García

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 1, 2024

Abstract Dysfunction in fast-spiking parvalbumin interneurons (PV-INs) may represent an early pathophysiological perturbation Alzheimer’s Disease (AD). Defining proteomic alterations PV-INs can provide key biological and translationally-relevant insights. We used cell-type-specific in-vivo biotinylation of proteins (CIBOP) coupled with mass spectrometry to obtain native-state PV-IN proteomes. signatures include high metabolic translational activity, over-representation AD-risk cognitive resilience-related proteins. In bulk proteomes, were associated decline humans, progressive neuropathology humans the 5xFAD mouse model Aβ pathology. CIBOP stages pathology revealed increased mitochondria metabolism, synaptic cytoskeletal disruption decreased mTOR signaling, not apparent whole-brain Furthermore, we demonstrated pre-synaptic defects PV-to-excitatory neurotransmission, validating our findings. Overall, this study present proteomes PV-INs, revealing molecular insights into their unique roles resiliency AD pathogenesis.

Language: Английский

Citations

22
Enteric glutamatergic interneurons regulate intestinal motility DOI Creative Commons
Ryan Hamnett, Jacqueline L. Bendrick,

Zinnia Saha

et al.

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

3
Synapse-type-specific competitive Hebbian learning forms functional recurrent networks DOI Creative Commons
Samuel Eckmann, Edward Young, Julijana Gjorgjieva

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(25)

Published: June 13, 2024

Cortical networks exhibit complex stimulus–response patterns that are based on specific recurrent interactions between neurons. For example, the balance excitatory and inhibitory currents has been identified as a central component of cortical computations. However, it remains unclear how required synaptic connectivity can emerge in developing circuits where synapses neurons simultaneously plastic. Using theory modeling, we propose wide range response properties arise from single plasticity paradigm acts at all connections—Hebbian learning is stabilized by synapse-type-specific competition for limited supply resources. In plastic circuits, this enables formation decorrelation inhibition-balanced receptive fields. Networks develop an assembly structure with stronger connections similarly tuned normalization orientation-specific center-surround suppression, reflecting stimulus statistics during training. These results demonstrate self-organize into functional suggest essential role competitive development circuits.

Language: Английский

Citations

9
Neuron type-specific mRNA translation programs provide a gateway for memory consolidation. DOI Creative Commons
Maurício M. Oliveira, Olivia Mosto, Robert M. Carney

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Summary Long-term memory consolidation is a dynamic process that requires heterogeneous ensemble of neurons, each with highly specialized molecular environment. Considerable effort has been placed into understanding how the mechanisms in specific neuron types are modified memory, but these studies often undertaken hours or days after training, when already consolidated. Studies have shown protein synthesis elevated during early stages consolidation, there limited information as to it impacts neuronal function. We hypothesize mRNAs being translated could provide clues diverse neurons involved formation restructure their architecture support formation. Here, we generate landscape translatome three dorsal hippocampus first hour contextual consolidation. Our results show share common backbone readily mRNAs. However, excitatory undergo deep reconfiguration proteostatic control, whereas interneurons modify synaptic transmission. demonstrate translational control GADD34, which promotes translation initiation. Finally, differential expression by can be explained features hard coded mRNA, suggesting ubiquitous controlling activity-dependent translation. Altogether, our work uncovers previously unknown checkpoints and provides large, available resource for further investigations health disease.

Language: Английский

Citations

1
Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders DOI Creative Commons
Mei Yuan, Maya L. Gosztyla,

Xinzhu Tan

et al.

Cell Systems, Journal Year: 2025, Volume and Issue: unknown, P. 101204 - 101204

Published: March 1, 2025

Language: Английский

Citations

1
Most axonal mitochondria in cortical pyramidal neurons lack mitochondrial DNA and consume ATP DOI Creative Commons
Yusuke Hirabayashi, Tommy L. Lewis,

Yudan Du

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 13, 2024

Abstract In neurons of the mammalian central nervous system (CNS), axonal mitochondria are thought to be indispensable for supplying ATP during energy-consuming processes such as neurotransmitter release. Here, we demonstrate using multiple, independent, in vitro and vivo approaches that majority (∼80-90%) cortical pyramidal (CPNs), lack mitochondrial DNA (mtDNA). Using dynamic, optical imaging analysis genetically encoded sensors matrix pH, axons CPNs, but not their dendrites, complex V (ATP synthase) functions a reverse way, consuming protruding H + out maintain membrane potential. Our results do play major role supply, despite playing other critical regulating neurotransmission Ca 2+ buffering.

Language: Английский

Citations

5
An atlas of protein-protein associations of human tissues prioritizes candidate disease genes DOI Creative Commons
Diederik S. Laman Trip, Marc van Oostrum, Danish Memon

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 17, 2024

Abstract Proteins that interact together participate in the same cellular process and influence organismal traits. Despite progress mapping protein-protein interactions we lack knowledge of how they differ between tissues. Due to coordinated (post)transcriptional control, protein complex members have highly correlated abundances are predictive functional association. Here, compiled 7873 proteomic samples measuring levels 11 human tissues use these define an atlas with tissue-specific associations. This method recapitulates known complexes larger structural organization cell. Interactions stable well preserved across tissues, while signaling metabolic show variation. Further, find less than 18% differences estimated be due gene expression cell-type specific structures, such as synaptic components, represent a significant driver We further supported brain association network through co-fractionation experiments synaptosomes, curation derived pull-down data AlphaFold2 models. Together results illustrate this interaction can functionally prioritize candidate genes within loci linked disorders.

Language: Английский

Citations

4
Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition DOI Creative Commons
Baptiste Libé‐Philippot, Ryohei Iwata, Aleksandra J. Recupero

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(21), P. 3602 - 3617.e9

Published: Oct. 14, 2024

Human-specific (HS) genes have been implicated in brain evolution, but their impact on human neuron development and diseases remains unclear. Here, we study SRGAP2B/C, two HS gene duplications of the ancestral synaptic SRGAP2A, cortical pyramidal neurons (CPNs) xenotransplanted mouse cortex. Downregulation SRGAP2B/C CPNs led to strongly accelerated development, indicating requirement for neoteny that distinguishes synaptogenesis. promoted by reducing levels SRGAP2A,thereby increasing postsynaptic accumulation SYNGAP1 protein, encoded a major intellectual disability/autism spectrum disorder (ID/ASD) gene. Combinatorial loss-of-function experiments vivo revealed tempo synaptogenesis is set reciprocal antagonism between SRGAP2A SYNGAP1, which tipped toward SRGAP2B/C. Thus, can modify phenotypic expression genetic mutations leading ID/ASD through regulation neoteny.

Language: Английский

Citations

4
Synaptoneurolipidomics: lipidomics in the study of synaptic function DOI Creative Commons
Robert Ahrends, Shane R. Ellis, Steven H. L. Verhelst

et al.

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

The brain is an exceptionally lipid-rich organ with a very complex lipid composition. Lipids are central in several neuronal processes, including membrane formation and fusion, myelin packing, lipid-mediated signal transmission. Lipid diversity associated the evolution of higher cognitive abilities primates, affected by activity, instrumental for synaptic plasticity, illustrating that lipids not static components membranes. Several lines evidence suggest composition synapses unique distinct from other subcompartments. Here, we delve into nascent field synaptoneurolipidomics, offering overview current knowledge on junctions technological advances will allow us to study impact function.

Language: Английский

Citations

0
Understanding GABAergic synapse diversity and its implications for GABAergic pharmacotherapy DOI Creative Commons
Dilja Krueger‐Burg

Trends in Neurosciences, Journal Year: 2025, Volume and Issue: 48(1), P. 47 - 61

Published: Jan. 1, 2025

Despite the substantial contribution of disruptions in GABAergic inhibitory neurotransmission to etiology psychiatric, neurodevelopmental, and neurodegenerative disorders, surprisingly few drugs targeting system are currently available, partly due insufficient understanding circuit-specific synapse biology. In addition GABA receptors, synapses contain an elaborate organizational protein machinery that regulates properties synaptic transmission. Until recently, this remained largely unexplored, but key methodological advances have now led identification a wealth new organizer proteins. Notably, many these proteins appear function only at specific subsets synapses, creating diversity complexes may serve as targets for pharmacotherapies. The present review aims summarize developments underlie newfound knowledge provide current overview synapse-specific complexes, well outlining future avenues challenges translating into clinical applications.

Language: Английский

Citations

0