Biology subjects

Scheuss, V.

Publications and source records attributed to Scheuss, V..

5 recordsLinked to original sources

bioRxiv2024

Modulation of Neuronal Excitability and Plasticity by BHLHE41 Conveys Lithium Non-Responsiveness

Many bipolar disorder (BD) patients are non-responsive to lithium. The mechanisms underlying lithium (non-)responsiveness are largely unknown. By using gene-set enrichment analysis methods, we found that core clock gene-sets are significantly associated with lithium response. Among the top hits was BHLHE41, a modulator of the molecular clock and homeostatic sleep. Since BHLHE41 and its paralog BHLHE40 are functionally redundant, we assessed chronic lithium response in double-knockout mutant mice (DKO). We demonstrated that DKOs are non-responsive to lithiums effect in various behavioral tasks. Cellular assays and patch clamp recordings revealed lowered excitability and reduced lithium-response in prefrontal cortical layer 2/3 DKO neurons and on hippocampal long-term potentiation. Single-cell RNA sequencing identified that lithium deregulated mitochondrial respiration, cation channel and postsynapse associated gene-sets specifically in upper layer excitatory neurons. Our findings show that lithium acts in a highly cell-specific way on neuronal metabolism and excitability and modulates synaptic plasticity depending on BHLHE40/41.

neuroscience↗

bioRxiv2024

Polygenic risk for schizophrenia converges on alternative polyadenylation as molecular mechanism underlying synaptic impairment

Schizophrenia (SCZ) is a genetically heterogenous psychiatric disorder of highly polygenic nature. Correlative evidence from genetic studies indicate that the aggregated effects of distinct genetic risk factor combinations found in each patient converge onto common molecular mechanisms. To prove this on a functional level, we employed a reductionistic cellular model system for polygenic risk by differentiating induced pluripotent stem cells (iPSCs) from 104 individuals with high polygenic risk load and controls into cortical glutamatergic neurons (iNs). Multi-omics profiling identified widespread differences in alternative polyadenylation (APA) in the 3 untranslated region of many synaptic transcripts between iNs from SCZ patients and healthy donors. On the cellular level, 3APA was associated with a reduction in synaptic density of iNs. Importantly, differential APA was largely conserved between postmortem human prefrontal cortex from SCZ patients and healthy donors, and strongly enriched for transcripts related to synapse biology. 3APA was highly correlated with SCZ polygenic risk and affected genes were significantly enriched for SCZ associated common genetic variation. Integrative functional genomic analysis identified the RNA binding protein and SCZ GWAS risk gene PTBP2 as a critical trans-acting factor mediating 3APA of synaptic genes in SCZ subjects. Functional characterization of PTBP2 in iNs confirmed its key role in 3APA of synaptic transcripts and regulation of synapse density. Jointly, our findings show that the aggregated effects of polygenic risk converge on 3APA as one common molecular mechanism that underlies synaptic impairments in SCZ.

neuroscience↗

bioRxiv2021

Functional and structural features of L2/3 pyramidal cells continuously covary with pial depth in mouse visual cortex

Pyramidal cells of neocortical layer 2/3 (L2/3 PyrCs) integrate signals from numerous brain areas and project throughout the neocortex. Within L2/3, PyrCs show functional and structural specializations depending on their pial depth, indicating participation in different functional microcircuits. However, it is unknown whether these depth-dependent differences result from separable L2/3 PyrC subtypes or whether functional and structural features represent a continuum while correlating with pial depth. Here, we assessed the stimulus selectivity, electrophysiological properties, dendritic morphology, and excitatory and inhibitory synaptic connectivity across the depth of L2/3 in the binocular visual cortex (bV1) of female mice. We find that the structure of the apical but not the basal dendritic tree varies with pial depth, which is accompanied by differences in passive but not active electrophysiological properties. PyrCs in lower L2/3 receive increased excitatory and inhibitory input from L4, while upper L2/3 PyrCs receive a larger proportion of intralaminar input. Complementary in vivo calcium imaging revealed a systematic change in visual responsiveness, with deeper L2/3 PyrCs showing more robust responses than superficial PyrCs. Furthermore, deeper L2/3 PyrCs are more strongly driven by contralateral than ipsilateral eye stimulation. In contrast, orientation- and direction-selectivity of L2/3 PyrCs are not dependent on pial depth. Importantly, the transitions of the various properties are gradual, and cluster analysis does not support the classification of L2/3 PyrCs into discrete subtypes. These results show that L2/3 PyrCs multiple functional and structural properties systematically correlate with their depth within L2/3, forming a continuum rather than representing discrete subtypes. SIGNIFICANCE STATEMENTNeocortical pyramidal cells in layer 2/3 (L2/3 PyrCs) are crucial for cortical computation and display heterogenous properties. We investigated whether and how these properties vary across the depth of L2/3 and whether L2/3 PyrCs can be subdivided into distinct subtypes. This is important for a better understanding of the coding strategy and information integration processes within L2/3. We find that multiple properties such as morphology, physiology, connectivity, and functional in vivo responses of L2/3 PyrCs correlate with cortical depth in mouse visual cortex. These variations are continuous and do not support classification of L2/3 PyrCs into discrete subtypes. In contrast to L5 and L6, PyrCs in L2/3 therefore process information based on a continuous property space.

neuroscience↗

bioRxiv2020

Selective connectivity limits functional binocularity in the retinogeniculate pathway of the mouse

Eye-specific segregation of retinal ganglion cell (RGC) axons in the dorsal lateral geniculate nucleus (dLGN) is considered a hallmark of visual system development. However, a recent anatomical study showed that nearly half of the neurons in dLGN of adult mice still receive input from both retinae, but functional data about binocularity in mature dLGN is conflicting. Here, we found that a variable but small fraction of thalamocortical neurons is binocular in vivo. Using dual-channel optogenetics in vitro we correspondingly found that dLGN neurons are dominated by retinogeniculate input from one eye only, although most neurons also received small but detectable input from the non-dominant eye. Anatomical overlap between RGC axons and dLGN neuron dendrites did not explain this strong bias towards monocularity. Our data rather suggest that functional input selection and refinement, leaving the remaining non-dominant eye inputs in a juvenile-like state, underlies the prevalent monocularity of neurons in dLGN.

neuroscience↗

bioRxiv2020

Relationship between input connectivity, morphology and orientation tuning of layer 2/3 pyramidal cells in mouse visual cortex

Neocortical pyramidal cells (PCs) display functional specializations defined by their excitatory and inhibitory circuit connectivity. For layer 2/3 (L2/3) PCs, little is known about the detailed relationship between their neuronal response properties, dendritic structure and their underlying circuit connectivity at the level of single cells. Here, we ask whether L2/3 PCs in mouse primary visual cortex (V1) differ in their functional intra- and interlaminar connectivity patterns, and how this relates to differences in visual response properties. Using a combined approach, we first characterized the orientation and direction tuning of individual L2/3 PCs with in vivo 2-photon calcium imaging. Subsequently, we performed excitatory and inhibitory synaptic input mapping of the same L2/3 PCs in brain slices using laser scanning photostimulation (LSPS). Our data from this structure-connectivity-function analysis show that the sources of excitatory and inhibitory synaptic input are different in their laminar origin and horizontal location with respect to cell position: On average, L2/3 PCs receive more inhibition than excitation from within L2/3, whereas excitation dominates input from L4 and L5. Horizontally, inhibitory input originates from locations closer to the horizontal position of the soma, while excitatory input arises from more distant locations in L4 and L5. In L2/3, the excitatory and inhibitory inputs spatially overlap on average. Importantly, at the level of individual neurons, PCs receive inputs from presynaptic cells located spatially offset, vertically and horizontally, relative to the soma. These input offsets show a systematic correlation with the preferred orientation of the postsynaptic L2/3 PC in vivo. Unexpectedly, this correlation is higher for inhibitory input offsets within L2/3 than for excitatory input offsets. When relating the dendritic complexity of L2/3 PCs to their orientation tuning, we find that sharply tuned cells have a less complex apical tree compared to broadly tuned cells. These results indicate that the spatial input offsets of the functional input connectivity are linked to orientation preference, while the orientation selectivity of L2/3 PCs is more related to the dendritic complexity.

neuroscience↗