Biology subjects

Kreutzmann, J. C.

Publications and source records attributed to Kreutzmann, J. C..

4 recordsLinked to original sources

bioRxiv2026

Dissection of neuropsychiatric-relevant behavioral and structural phenotypes utilizing neuron type-specific ablation of the Bassoon gene in mice

Rare pathogenic mutations in the human BSN gene, which encodes the presynaptic cytomatrix protein Bassoon-a key organizer of the neurotransmitter release apparatus have been linked to neuropsychiatric conditions including schizophrenia. Here we began to dissect the potential contribution of Bsn deficiency in distinct populations of mouse (fore)brain neurons on behavioral and anatomical alterations resembling schizophrenia-like phenotypes. To this end, conditional knockout mice lacking Bassoon in subsets of inhibitory synapses (BsnDlx5/6cKO), in forebrain excitatory synapses (BsnEmx1cKO), or at dopaminergic release sites (BsnDATcKO) were generated. The mice were assessed using prepulse inhibition, a paradigm that models sensorimotor gating, which is often impaired in schizophrenia, and a fear/safety learning paradigm. Further, anxiety-related behaviors were evaluated and magnetic resonance imaging (MRI) was performed to assess anatomical brain alterations. Our data reveal synapse-specific effects of the Bassoon deficiency. Sensory gating deficits were observed in both BsnDlx5/6cKO and BsnEmx1cKO mice. BsnDlx5/6cKO mice further demonstrated impaired discrimination between conditioned fear and safety-a condition frequently observed in individuals with schizophrenia. By contrast, BsnDATcKO mice displayed enhanced discrimination between conditioned fear and safety. All mouse strains showed elevated anxiety-like behavior in the light/dark box. Structural MRI revealed increased brain volumes in BsnDlx5/6cKO and BsnEmx1cKO mice, with the most pronounced changes in the hippocampus and cortex. Previous studies have shown that BsnDlx5/6cKO mice display autistic-like behaviors, altered hippocampal network activity and epilepsy. Our findings support the notion that deficits in Bsn-mediated functions, particularly in interneurons, may contribute to the etiology of neurodevelopmental and neuropsychiatric conditions.

neuroscience↗

bioRxiv2025

Autism-like behavior induced by conditional ablation of the Bassoon gene in GABAergic interneurons

Synaptic dysfunction and resulting imbalance of excitatory vs. inhibitory transmission are fundamental aspects of autism spectrum disorders (ASD). Here we addressed the role of inhibitory synapse disturbances in ASD employing mice with a conditional ablation in inhibitory forebrain interneurons of the presynaptic active zone scaffolding protein Bassoon (Bsn), a key factor in synaptic development, activity and maintenance. The conditional Bsn gene knock out resulted in a reduction of synaptic vesicles and reduced synaptic efficacy of affected inhibitory synapses as well as diminished GABAergic inhibition in hippocampal pyramidal neurons. Bsn mutants further displayed a reconfiguration of the hippocampal synaptic network in vivo, as seen in subfield-specific changes of inhibitory synaptic markers and reduced numbers of parvalbumin interneurons, culminating in disturbance of hippocampal network activity patterns and profound mitochondrial and metabolic dysregulation. Importantly, the mutant mice developed behavioral abnormalities reminiscent of ASD including widespread social behavioral deficits and novelty-induced hyperarousal with altered motor behavior, increased anxiety and epileptiform activity. Bsn conditional knock out mice thus provide strong evidence for a causal involvement of GABAergic synapses in the emergence of ASD-related behavioral and physiological phenotypes.

neuroscience↗

bioRxiv2025

Development of a protocol utilizing single-cell analysis for the differentiation of human iPSCs into SOX6+ midbrain dopaminergic neurons.

Parkinsons disease (PD) is characterized by the progressive loss of midbrain dopaminergic (mDA) neurons, leading to severe debilitating motor impairment. Recent single-cell analyses have revealed that specific mDA subpopulations, such as SOX6 AGTR1 neurons, are most vulnerable to degeneration. Current human pluripotent stem cell differentiation protocols fail to selectively generate these subtypes. Here, we describe a multiomic-guided strategy that enriches SOX6+ mDA neurons by combining enhancing Sonic Hedgehog agonism with prolonged Wnt activation. This approach accelerates floor plate specification, increases expression of mDA developmental markers, and substantially increases the yield of SOX6 mature mDA neurons compared to prior attempts. Following intrastriatal transplantation into hemiparkinsonian mice, these cells restored motor function in approximately 4 months and generated grafts containing SOX6 A9-like neurons. Our work thus establishes a reproducible differentiation platform for generating the PD-susceptible mDA subtype, providing a foundation for precision disease modelling and subtype-targeted cell replacement therapies.

cell biology↗

bioRxiv2022

Whole-Brain Three-Dimensional Imaging of RNAs at Single-Cell Resolution

Whole-brain three-dimensional (3D) imaging is desirable to obtain a comprehensive and unbiased view of architecture and neural circuitry. However, current spatial analytic methods for brain RNAs are limited to thin sections or small samples. Here, we combined multiple new techniques to develop TRIC-DISCO, a new pipeline that allows imaging of RNA spatial distributions in whole adult mouse brains. First, we developed Tris-mediated retention of in situ hybridization signal during clearing (TRIC), which produces highly transparent tissue while maintaining the RNA signal intensities. We then combined TRIC with DISCO clearing (TRIC-DISCO) by controlling temperature during the in situ hybridization chain reaction (isHCR) to ensure uniform whole-brain staining. This pipeline eliminates the requirements for both strict RNase-free environments and workflow-compatible RNase inhibitors. Our TRIC-DISCO pipeline enables simple and robust, single-cell, whole-brain, 3D imaging of transcriptional signatures, cell-identity markers, and noncoding RNAs across the entire brain.

neuroscience↗