Biology subjects

Scheiffele, P.

Publications and source records attributed to Scheiffele, P..

8 recordsLinked to original sources

bioRxiv2026

Principles of NMDA receptor co-agonism at cortical fast-spiking GABAergic interneurons in the adolescent prefrontal cortex

N-methyl-D-aspartate receptors (NMDARs) populate fast-spiking (FS)-parvalbumin-positive (PV+) GABAergic interneurons (INs), where they play a critical role in shaping circuit motifs and memory. However, it is largely unknown whether and how NMDARs at FS-PV+-INs are gated by their co-agonists and the functional relevance of such modulations for their synaptic coupling with excitatory neurons. Here, we report that FS-PV+-INs in the adolescent mouse prefrontal cortex, an area central to complex cognitive operation exhibit functional GluN2B/D containing NMDARs. These receptors contribute to the excitatory drive of FS-PV+-INs and to the feedforward inhibition, controlling short-term and long-term synaptic plasticity. While the identity of the co-agonist controlling GABAergic tone is tuned by the synaptic activity regime from D-serine to glycine, we reveal that it remains largely unchanged at the excitatory synapse with D-serine being the sole co-agonist gating NMDARs. Lastly, we show that D-serine-deficient mice, a model of NMDAR hypofunction show selective attenuation of PV+-INs excitation together with selective loss of temporal summation and long-term plasticity at the excitatory synapse. Our study reveals the segregation of pools of NMDARs at the soma and dendrites that are differently sensitive to D-serine or glycine, the existence of distinct modes of activity-dependent regulation of these NMDARs by their co-agonists at this major type of GABAergic INs, and hence the rules governing cortical inhibition by FS-PV+-INs during a critical period of late postnatal development.

neuroscience↗

bioRxiv2024

A ternary Neurexin-T178-PTPR complex represents a core-module of neuronal synapse organization

The organization of cell-cell contacts is fundamental for multi-cellular life and operation of organs. Synapses, prototypic contact sites for neuronal communication, are key to brain function and work over the last decades identified multiple synaptic cell adhesion molecules (sCAMs) that drive their organization. Whether these sCAMs operate independently or in coordination through yet unknown linker proteins remained elusive. Here, we used a systematic large-scale multi-epitope affinity-purification approach combined with quantitative mass spectrometry and immuno-EM to comprehensively map trans-synaptic protein networks in the mouse brain. We discover a presynaptic core-module assembled from the two major sCAM families, Neurexins1-3 and LAR-type receptor protein tyrosine phosphatases (PTPRD,S,F), and the previously uncharacterized tetraspanin proteins T178A, B. These ternary Neurexin-T178-PTPR complexes form through their trans-membrane domains and assemble during biogenesis in the ER. Loss of T178B results in module dissociation, strong reduction of LAR-PTPRs and re-distribution of synaptic Neurexins. At synapses, the Neurexin-T178-PTPR module recruits stable and extended trans-synaptic protein networks with defined pre- and post-synaptic partners and secreted extracellular linkers. The network architecture robustly interlinks the distinct functional modules/machineries of the presynaptic active zone and establishes tight associations with XKR-type lipid scramblases and postsynaptic GABAergic and glutamatergic neurotransmitter receptors. Our data identify a universal presynaptic core-module for synaptic adhesion and trans-synaptic signaling in the mammalian brain.

neuroscience↗

bioRxiv2023

Dilated cardiomyopathy-associated RNA Binding Motif Protein 20 regulates long pre-mRNAs in neurons

Precise coordination of molecular programs and neuronal growth govern the formation, maintenance, and adaptation of neuronal circuits. RNA metabolism has emerged as a key regulatory node of neural development and nervous system pathologies. To uncover cell-type-specific RNA regulators, we systematically investigated expression of RNA recognition motif-containing proteins in the mouse neocortex. Surprisingly, we found RBM20, an alternative splicing regulator associated with dilated cardiomyopathy, to be expressed in cortical parvalbumin interneurons and mitral cells of the olfactory bulb. Genome-wide mapping of RBM20 target mRNAs revealed that neuronal RBM20 binds pre-mRNAs in distal intronic regions. Loss of neuronal RBM20 has only modest impact on alternative splice isoforms but results in a significant reduction in an array of mature mRNAs in the neuronal cytoplasm. This phenotype is particularly pronounced for genes with long introns that encode synaptic proteins. We hypothesize that RBM20 ensures fidelity of pre-mRNA splicing by suppressing non-productive splicing events in long neuronal genes. This work highlights a common requirement for RBM20-dependent transcriptome regulation in cardiomyocytes and neurons and demonstrates that a major genetic risk factor of heart disease impacts neuronal gene expression.

neuroscience↗

bioRxiv2023

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling

Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific disruption of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation - inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.

neuroscience↗

bioRxiv2022

Trans-cellular control of synapse properties by a cell type-specific splicing regulator

The recognition of synaptic partners and specification of synaptic properties are fundamental for the function of neuronal circuits. Terminal selector transcription factors coordinate the expression of terminal gene batteries that specify cell type-specific properties. Moreover, pan-neuronal alternative splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell type-specific loss-of-function studies to uncover the contribution of the nuclear RNA binding protein SLM2 to hippocampal synapse specification. Focusing on hippocampal pyramidal cells and SST-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins, thereby generating cell type-specific isoforms. In the absence of SLM2, cell type-specification, differentiation, and viability are unaltered and neuronal populations exhibit normal intrinsic properties. By contrast, cell type-specific loss of SLM2 results in highly selective, non-cell autonomous synaptic phenotypes, altered synaptic transmission, and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner.

neuroscience↗

bioRxiv2022

Cell type-specific assessment of cholesterol distribution in models of neurodevelopmental disorders

Most nervous system disorders manifest through alterations in neuronal signaling based on abnormalities in neuronal excitability, synaptic transmission, and cell survival. However, such neuronal phenotypes are frequently accompanied - or even caused - by metabolic dysfunctions in neuronal or non-neuronal cells. The tight packing and highly heterogenous properties of neural, glial and vascular cell types pose significant challenges to dissecting metabolic aspects of brain disorders. Perturbed cholesterol homeostasis has recently emerged as key parameter associated with sub-sets of neurodevelopmental disorders. However, approaches for tracking and visualizing endogenous cholesterol distribution in the brain have limited capability of resolving cell type-specific differences. We here develop tools for genetically-encoded sensors that report on cholesterol distribution in the mouse brain with cellular resolution. We apply these probes to examine sub-cellular cholesterol accumulation in two genetic mouse models of neurodevelopmental disorders, Npc1 and Ptchd1 knock-out mice. While both genes encode proteins with sterol-sensing domains that have been implicated in cholesterol transport, we uncover highly selective and cell type-specific phenotypes in cholesterol homeostasis. The tools established in this work should facilitate probing sub-cellular cholesterol distribution in complex tissues like the mammalian brain and enable capturing cell type-specific alterations in cholesterol flow between cells in models of brain disorders.

neuroscience↗

bioRxiv2021

Cue-specific remodeling of the neuronal transcriptome through intron retention programs

Sub-cellular compartmentalization through the nuclear envelope has for a long time been primarily considered a physical barrier that separates nuclear and cytosolic contents. More recently, nuclear compartmentalization has emerged to harbor key regulatory functions in gene expression. A sizeable proportion of protein-coding mRNAs is more prevalent in the nucleus than in the cytosol reflecting the existence of mechanisms to control mRNA release into the cytosol. However, the biological relevance of the nuclear retention of mRNAs remains unclear. Here, we provide a comprehensive map of the subcellular localization of mRNAs in mature neurons and reveal that transcripts stably retaining introns are broadly targeted for nuclear retention. We systematically probed these transcripts upon neuronal stimulation and found that sub-populations of nuclear-retained transcripts are bi-directionally regulated in response to cues: some appear targeted for degradation while others undergo splicing completion to generate fully mature mRNAs which are exported to the cytosol to increase functional gene expression. Remarkably, different forms of stimulation mobilize distinct groups of intron-retaining transcripts and this selectivity arises from the activation of specific signaling pathways. Overall, our findings uncover cue-specific control of intron retention as a major regulator of acute remodeling of the neuronal transcriptome.

neuroscience↗

bioRxiv2018

Neuronal signature of social novelty exploration in the VTA: implication for Autism Spectrum Disorder

Novel stimuli attract our attention, promote exploratory behavior, and facilitate learning. Atypical habituation and aberrant novelty exploration have been related with the severity of Autism Spectrum Disorders (ASD) but the underlying neuronal circuits are unknown. Here, we report that dopamine (DA) neurons of the ventral tegmental area (VTA) promote the behavioral responses to novel social stimuli, support preference for social novelty, and mediate the reinforcing properties of novel social interaction. Social novelty exploration is associated with the insertion of calcium-permeable GluA2-lacking AMPA-type glutamate receptors at excitatory synapses on VTA DA neurons. These novelty-dependent synaptic adaptations only persist upon repeated exposure to social stimuli and sustain social interaction. Global or DA neuron-specific inactivation of the ASD risk gene Neuroligin3 alters both social novelty exploration and the reinforcing properties of social stimuli. These behavioral deficits are accompanied by an aberrant expression of non-canonical GluA2-lacking AMPA-receptors at excitatory synapses on VTA DA neurons and an occlusion of novelty-induced synaptic plasticity. Altogether, these findings causally link impaired novelty exploration in an ASD mouse model to VTA DA circuit dysfunction.

neuroscience↗