Synaptic recognition molecules in development and disease

Chowdhury, Dhrubajyoti; Watters, Katherine; Biederer, Thomas

doi:10.1016/bs.ctdb.2020.12.009

Cited by 15 publications

(21 citation statements)

References 265 publications

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“…However, a third process also needs to be considered for synapse specificity: shaping of the properties of synapses that are as important for the overall performance of a neural circuit as the number and location of the synapses. These three processes collaborate to achieve the exquisite specificity of synapse formation ( Südhof, 2018 ; Sanes and Zipursky, 2020 ; Chowdhury et al, 2021 ).…”

Section: Sams and Synaptic Specificitymentioning

confidence: 99%

The cell biology of synapse formation

Südhof¹

2021

Journal of Cell Biology

170

129

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In a neural circuit, synapses transfer information rapidly between neurons and transform this information during transfer. The diverse computational properties of synapses are shaped by the interactions between pre- and postsynaptic neurons. How synapses are assembled to form a neural circuit, and how the specificity of synaptic connections is achieved, is largely unknown. Here, I posit that synaptic adhesion molecules (SAMs) organize synapse formation. Diverse SAMs collaborate to achieve the astounding specificity and plasticity of synapses, with each SAM contributing different facets. In orchestrating synapse assembly, SAMs likely act as signal transduction devices. Although many candidate SAMs are known, only a few SAMs appear to have a major impact on synapse formation. Thus, a limited set of collaborating SAMs likely suffices to account for synapse formation. Strikingly, several SAMs are genetically linked to neuropsychiatric disorders, suggesting that impairments in synapse assembly are instrumental in the pathogenesis of neuropsychiatric disorders.

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Section: Sams and Synaptic Specificitymentioning

confidence: 99%

The cell biology of synapse formation

Südhof¹

2021

Journal of Cell Biology

170

129

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“…We filtered our differential expression results using the gene ontology (GO) software PANTHER 16.0 (Mi et al, 2021) to select genes labeled by the terms “Cell-cell adhesion”, “Regulation of cell-cell adhesion”, and “Regulation of trans-synaptic signaling”. These were chosen because they include genes related to the formation, maintenance, and modulation of synaptic connections among distinct neuronal subtypes (Fuccillo et al, 2015;Földy et al, 2016;Chowdhury et al, 2021). Throughout, we refer to these as “circuit-related” genes.…”

Section: Resultsmentioning

confidence: 99%

“…5Cii ). Finally, dysregulation of circuit-related genes directly contributes to neurological disorders (Chowdhury et al, 2021). Thus, we highlighted in green candidate risk genes for autism using the SFARI Human Gene Module (https://gene.sfari.org/database/human-gene/) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A challenge to understanding ASD is its broad range of conditions involving impairments in social-communication, cognitive, and sensorimotor functions (Marco et al, 2011;Whyatt and Craig, 2013;Donovan and Basson, 2017). This is likely attributed to disruptions in neural circuits across multiple brain regions including the neocortex (Marco et al, 2011;Donovan and Basson, 2017;Velmeshev et al, 2019;Chowdhury et al, 2021). Identifying genetic disruptions that impair circuitry across regions and pinpointing specific types of neurons that are affected is crucial.…”

Section: Discussionmentioning

confidence: 99%

“…A challenge to understanding ASD is its broad range of impairments in social-communication, cognition, and sensorimotor functions, due to disruptions in neural circuits across the brain (Marco et al, 2011;Whyatt and Craig, 2013;Donovan and Basson, 2017;Velmeshev et al, 2019;Chowdhury et al, 2021). A prominent hypothesis is that an imbalance in the ratio of excitation to inhibition (E/I) corrupts information processing within these circuits, leading to pathology (Rubenstein and Merzenich, 2003;Sohal and Rubenstein, 2019).…”

Section: Discussionmentioning

confidence: 99%

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Cell-type specific transcriptomic signatures of neocortical circuit organization and their relevance to autism

Moussa

Wester

2022

Preprint

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A prevailing challenge in neuroscience is understanding how diverse neuronal cell types select their synaptic partners to form circuits. In the neocortex, major subclasses of excitatory projection neurons and inhibitory interneurons are conserved across functionally distinct regions. There is evidence these subclasses form circuits that depend primarily on their identity; however, regional cues likely also influence their choice of synaptic partners. We mined the Allen Brain Institute's single-cell RNA-sequencing database of mouse cortical neurons to study the expression of cellular adhesion molecules (CAMs) necessary for synapse formation in two regions: the anterior lateral motor cortex (ALM) and the primary visual cortex (VISp). We used the Allen's metadata to parse cells by clusters representing major excitatory and inhibitory subclasses that are common to both ALM and VISp. We then performed two types of pairwise differential gene expression analysis: 1) between different neuronal subclasses within the same brain region (ALM or VISp), and 2) between the same neuronal subclass in ALM and VISp. We filtered our results for differentially expressed genes encoding CAMs and developed a novel bioinformatic approach to determine the sets uniquely enriched in each neuronal subclass in ALM, VISp, or both. This analysis provides an organized set of genes that may regulate circuit formation in a cell-type specific manner. Furthermore, it identifies candidate mechanisms for the formation of circuits that are conserved across functionally distinct cortical regions or that are region dependent. Finally, we used the SFARI Human Gene Module to identify CAMs from our analysis that are related to risk for autism spectrum disorder (ASD). From over 3,000 differentially expressed genes, we found 40 ASD-associated CAMs that are enriched in specific neuronal subclasses in both ALM and VISp. Our analysis provides clear molecular targets for future studies to understand neocortical circuit organization and abnormalities that underly autistic phenotypes.

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Emerging roles of planar cell polarity proteins in glutamatergic synapse formation, maintenance and function in health and disease

Freitas

Gorodetski

Lim

et al. 2023

Developmental Dynamics

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The local signaling mechanism which directly assembles and maintains glutamatergic synapses has not been well understood. Glutamatergic synapses are made of presynaptic and postsynaptic compartments with distinct sets of proteins. The planar cell polarity (PCP) pathway is highly conserved and responsible for establishing and maintaining the cell and tissue polarity along the tissue plane. The six core PCP proteins form antagonizing complexes within the cells and asymmetric intercellular complexes across neighboring cells which regulate cell‐cell interactions during planar polarity signaling. Accumulating evidence suggests that the PCP proteins play essential roles in glutamatergic synapse assembly, maintenance and function in the brain. This review summarizes the key evidence that PCP proteins may be responsible for the formation and stability of the vast majority of the glutamatergic synapses in hippocampus and medial prefrontal cortex, the progress in understanding the mechanisms of how PCP proteins assemble and maintain glutamatergic synapses and initial insights on how disruption of the function of the PCP proteins can lead to neurodegenerative, neurodevelopmental and neuropsychiatric disorders. The PCP proteins may be the missing pieces of a long‐standing puzzle and filling this gap of knowledge may provide the basis for understanding many unsolved questions in synapse biology.

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Synaptic recognition molecules in development and disease

Cited by 15 publications

References 265 publications

The cell biology of synapse formation

The cell biology of synapse formation

Cell-type specific transcriptomic signatures of neocortical circuit organization and their relevance to autism

Emerging roles of planar cell polarity proteins in glutamatergic synapse formation, maintenance and function in health and disease

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