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Synaptic Signatures and Disease Vulnerabilities of Layer 5 Pyramidal Neurons - second data set

ABSTRACT: Cortical layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons are embedded in distinct information processing pathways. The morphology, connectivity, electrophysiological properties, and role in behavior of these neurons have been extensively analyzed. However, the molecular composition of their synapses remains largely uncharacterized. Here, we dissect the protein composition of the excitatory postsynaptic compartment of L5 neurons in intact somatosensory circuits, using an optimized proximity biotinylation workflow with subsynaptic resolution. We find distinct synaptic signatures of L5 IT and PT neurons that are defined by proteins regulating synaptic organization and transmission, including cell-surface proteins (CSPs), neurotransmitter receptors and ion channels. In addition, we find a differential vulnerability to disease, with a marked enrichment of autism risk genes in the synaptic signature of L5 IT neurons compared to PT neurons. Our results align with human studies and suggest that the excitatory postsynaptic compartment of L5 IT neurons is notably susceptible in autism. Together, our analysis sheds light on the proteins that regulate synaptic organization and function of L5 neuron types and contribute to their susceptibility in disease. Our approach is versatile and can be broadly applied to other neuron types to create a protein-based, synaptic atlas of cortical circuits.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Andrew Howden

LAB HEAD: Professor Joris de Wit

PROVIDER: PXD052081 | Pride | 2024-11-04

REPOSITORIES: Pride

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			Action	DRS
	AH-1-1205-1-P.raw	Raw
	AH-11-1202-1-P.raw	Raw
	AH-13-1202-2-P.raw	Raw
	AH-15-1202-3-P.raw	Raw
	AH-17-No-virus-1.raw	Raw

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Cortical layer 5 neuron-specific synaptic protein profiling suggests differential vulnerability to neurodevelopmental disorders

Project description:Pyramidal neurons in the cortex are embedded in distinct information processing pathways. Cortical layer 5 (L5) intratelencephalic (IT) and pyramidal tract (PT) neurons receive different input and project to distinct brain regions. The synaptic molecular signatures that define synaptic connectivity and function of L5 IT and PT neurons are largely unknown. Here, we use an optimized proximity biotinylation workflow to characterize the excitatory postsynaptic proteomes of L5 IT and PT neurons in intact somatosensory circuits. We find that differential expression of neurotransmitter receptors, ion channels and cell-surface proteins (CSPs), most prominently of the leucine-rich repeat (LRR) family, specifies L5 IT and PT neuron input connectivity and function. Our analysis further uncovers differential vulnerability to neurodevelopmental disorders for L5 IT and PT neurons, with a marked enrichment of autism risk genes in the postsynaptic excitatory proteome of IT, but not of PT, neurons. Together, cell type- and input type-specific synaptic proteome profiling implies that many of the proteins specifying connectivity and function of two closely related cortical pyramidal cell types also underlie their differential vulnerability to neurodevelopmental disorders.

2024-11-04 | PXD046812 | Pride

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Homeodomain proteins hierarchically specify neuronal diversity and synaptic connectivity

Project description:How our brain generates diverse neuron types that assemble into precise neural circuits remains unclear. Using Drosophila lamina neuron types (L1-L5), we show that the primary homeodomain transcription factor (HDTF) Brain-specific homeobox (Bsh) is initiated in progenitors and maintained in L4/L5 neurons to adulthood. Bsh activates secondary HDTFs Ap (L4) and Pdm3 (L5) and specifies L4/L5 neuronal fates while repressing the HDTF Zfh1 to prevent ectopic L1/L3 fates (control: L1-L5; Bsh-knockdown: L1-L3), thereby generating lamina neuronal diversity for normal visual sensitivity. Subsequently, in L4 neurons, Bsh and Ap function in a feed-forward loop to activate the synapse recognition molecule DIP-β, thereby bridging neuronal fate decision to synaptic connectivity. Expression of a Bsh:Dam specifically in L4 reveals Bsh binding to the DIP-β locus and additional candidate L4 functional identity genes. We propose that HDTFs function hierarchically to coordinate neuronal molecular identity, circuit formation, and function. Hierarchical HDTFs may represent a conserved mechanism for linking neuronal diversity to circuit assembly and function.

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Complementary Expression of Immunoglobulin Superfamily Ligands and Receptors in Synaptic Pairs in the Drosophila Visual System

2015-12-17 | GSE68235 | GEO

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