Biology subjects

Gundelfinger, E. D.

Publications and source records attributed to Gundelfinger, E. D..

10 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↗

bioRxiv2026

Bassoon is required for adult ocular dominance plasticity and experience-induced changes in synapsin phosphorylation in visual cortex

Sensory stimulation enables experience-dependent fine tuning of brain circuits for optimal perception. In juvenile mice, brief closure of the contralateral eye reduces primary visual cortex (V1) activation through the deprived eye. In contrast, in adult animals, eye closure induces potentiated V1-responses to non-deprived eye visual stimulation. While considerable knowledge exists about postsynaptic mechanisms underlying this ocular dominance (OD) plasticity, little is known about contributing presynaptic molecules. Here we report that constitutive deletion of the presynaptic scaffolding protein bassoon (Bsn{Delta}Ex4/5) disrupted OD-plasticity in V1 of adult mice leaving juvenile OD-plasticity unaffected. Notably, in mice with a conditional deletion of Bsn only from cortical glutamatergic neurons (BsnEmx1), adult OD-plasticity was also impaired indicating that normal presynaptic plasticity of glutamatergic cortical synapses is selectively required in this process. While spatial vision was severely compromised in Bsn{Delta}Ex4/5 mice, it was preserved in BsnEmx1 mice, consistent with normal Bsn expression in subcortical circuit in these mice. Parallel experiments in cultured neurons revealed that deletion of Bsn left the inactivity-induced postsynaptic scaling of AMPA-responses mediated by increased AMPA receptor trafficking unchanged. However, presynaptic scaling was completely abolished as assessed by both electrophysiology and live-cell imaging of evoked synaptic vesicle fusion in cultured primary cortical neurons. Finally, monocular deprivation induced enhanced phosphorylation of synaptic vesicle-associated synapsin in contralateral V1 that was absent in BsnEmx1 mice. Overall, our data indicate that adult OD-plasticity requires Bsn-dependent presynaptic plasticity, involving experience-induced changes in synapsin phosphorylation. In contrast, juvenile OD-plasticity does not appear to be dependent on Bsn.

neuroscience↗

bioRxiv2025

Role of Bassoon-mediated active zone integrity at different types of brain synapses for brain activity and cortex-dependent memory formation

BackgroundThe properly controlled release of neurotransmitter at presynaptic active zones is crucial for brain function and performance. Bassoon is a major scaffolding protein involved in the organization of neurotransmitter release sites at excitatory, inhibitory and modulatory brain synapses. Global deficiency of functional Bassoon causes severe neurological conditions including disturbed patterns of brain activity and early-onset epilepsy. To distinguish the contribution of different types of synapses to this phenotype we generated conditional knockout (cKO) mice lacking the Bsn gene in (i) GABAergic interneurons expressing Cre recombinase under the control of the Dlx5/6 regulatory elements (BsnDlx5/6 cKO), (ii) glutamatergic forebrain neurons expressing Cre under the Emx1 promoter (BsnEmx1 cKO), and (iii) dopaminergic neurons expressing DAT-driven Cre (BsnDAT). MethodsSingle-photon emission computed tomography (SPECT) imaging of cerebral blood flow (CBF) was employed to assess in vivo brain-wide activation patterns in the cKO mice and corresponding control animals with wildtype Bsn genes. A cortex-dependent learning task to discriminate frequency-modulated tones was then used to evaluate the cognitive abilities of the different cKO lines. ResultsMarked reduction of brain activity was found in various cortical areas and the basolateral amygdala of BsnDlx5/6 cKO mice, while patches of increased activity were detected in the dorsal striatum. BsnEmx1 cKO mice, in contrast, display increased brain activity in many cortical areas. Only minor changes in CBF were detected in BsnDAT cKO mice. Concerning auditory discrimination learning BsnDlx5/6 cKO mice were severely impaired, although they responded to stimuli normally. On the other hand, BsnEmx1 cKO mice acquired the task more efficiently reaching maximum performance levels faster than control animals. Surprisingly, BsnDAT cKO mice did not differ in their behavior from the control group. ConclusionsOur data suggest that absence of Bassoon from presynapses of GABAergic interneurons expressing Dlx5/6 gene during development results in severe neurological symptoms and associated dysfunctions. Instead, network changes associated with Bassoon deficiency at glutamate release sites of excitatory forebrain neurons, even seem to have an enhancing effect on learning. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/690204v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@a5de5eorg.highwire.dtl.DTLVardef@1a9eeadorg.highwire.dtl.DTLVardef@174ccd1org.highwire.dtl.DTLVardef@132d92b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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↗

bioRxiv2023

Neural Extracellular Matrix Remodeling Signatures in Genetic and Acquired Mouse Models of Epilepsy

Epilepsies are multifaceted neurological disorders characterized by abnormal brain activity, e.g., caused by imbalanced synaptic excitation and inhibition. The neural extracellular matrix (ECM) is dynamically modulated by physiological and pathophysiological activity and critically involved in controlling the brains excitability. We used different epilepsy models, i.e. mice lacking the presynaptic scaffolding protein Bassoon at excitatory, inhibitory or all synapse types as genetic models for rapidly generalizing early-onset epilepsy, and intra-hippocampal kainate injection, a model for acquired temporal lobe epilepsy, to study the relationship between epileptic seizures and ECM composition. Electroencephalogram recordings revealed Bassoon deletion at excitatory or inhibitory synapses having diverse effects on epilepsy-related phenotypes. While constitutive Bsn mutants and GABAergic neuron-specific knockouts (BsnDlx5/6cKO) displayed severe epilepsy with more and stronger seizures than kainate-injected animals, mutants lacking Bassoon solely in excitatory forebrain neurons (BsnEmx1cKO) showed only mild impairments. By semiquantitative immunoblotting and immunohistochemistry we show model-specific patterns of neural ECM remodeling, and we also demonstrate significant upregulation of the ECM receptor CD44 in null and BsnDlx5/6cKO mutants. ECM-associated WFA-binding chondroitin sulfates were strongly augmented in seizure models. Strikingly, Brevican, Neurocan, Aggrecan and link protein Hapln1 levels reliably predicted seizure properties across models, suggesting a link between ECM state and epileptic phenotype.

neuroscience↗

bioRxiv2022

Monitoring regional astrocyte diversity by cell-type specific proteomic labeling in vivo

Astrocytes exhibit regional heterogeneity in morphology, function and molecular composition to support and modulate neuronal function and signaling in a region-specific manner. To characterize regional heterogeneity of astrocytic proteomes of different brain regions we established an Aldh1l1- MetRSL274G mouse line that allows cell-type specific labeling of newly synthesized proteins in vivo and analyzed astrocytic proteins from four different brain regions by mass spectrometry. Identified proteins are specific for astrocytes and show a high overlap with proteins compiled in AstroProt, a newly established database for astrocytic proteins. Gene enrichment analysis reveals high overlap among brain regions, and only subtle changes in abundances of key astrocytic proteins for hippocampus, cortex and striatum. However, the cerebellar proteome stands out with proteins being associated with calcium signaling or bipolar disorder. Subregional differences of translation dynamics in single hippocampal astrocytes indicates distinct subregional heterogeneity and highlights the applicability of our toolbox to study dynamic astrocytic proteomes in vivo.

neuroscience↗

bioRxiv2021

Bassoon controls synaptic vesicle pools via regulation of presynaptic phosphorylation and cAMP homeostasis

Neuronal presynaptic terminals contain hundreds of neurotransmitter-filled synaptic vesicles (SVs). The morphologically uniform SVs differ in their release competence segregating into functional pools that differentially contribute to neurotransmission. The presynaptic scaffold bassoon is required for neurotransmission, but the underlying molecular mechanisms are unknown. We report that glutamatergic synapses lacking bassoon featured a decreased SV release competence and increased resting pool of SV as observed by imaging of SV release in cultured neurons. Further analyses in vitro and in vivo revealed a dysregulation of CDK5/calcineurin and cAMP/PKA presynaptic signalling resulting in an aberrant phosphorylation of their downstream effectors synapsin 1 and SNAP25, which are well-known regulators of SV release competence. An acute pharmacological restoration of physiological CDK5 and cAMP/PKA activity fully normalised the SV pools in neurons lacking bassoon. Finally, we demonstrated that CDK5-dependent regulation of PDE4 activity controls SV release competence by interaction with cAMP/PKA signalling. These data reveal that bassoon organises SV pools via regulation of presynaptic phosphorylation and indicate an involvement of PDE4 in the control of neurotransmitter release.

neuroscience↗

bioRxiv2019

TRAF6 controls excitatory spinogenesis and excitation-inhibition balance thought binding neuroplastin

Synaptogenic mechanisms and their relevance to achieve a correct synapse density and activity in mature neurons are poorly understood. Here, we show that the tumor necrosis factor receptor-associated factor 6 (TRAF6) controls early spinogenesis by binding the cell adhesion molecule neuroplastin which is has been related to synapse formation in vivo. TRAF6-neuroplastin co-precipitations from brain samples and co-transfected HEK cells is explained by direct interaction of the proteins based on three-dimensional modelling and biochemical identification of intracellular amino acids of neuroplastin binding the TRAF-C domain of TRAF6 with micromolar affinity. TRAF6 was not only required for normal spinogenesis but also was strictly necessary to restore failed spinogenesis in neuroplastin-deficient neurons. Independently from neuroplastins extracellular adhesive properties or interaction with another known partner i.e. the plasma membrane Ca2+ ATPases, TRAF6 mediated formation of new postsynapses by neuroplastin overexpression in rat hippocampal neurons. Furthermore, TRAF6-controlled spinogenesis was required for the establishment of a correct synapse density as well as proper synaptic activity and intrinsic neuronal activity as demonstrated with intracellular and extracellular electrophysiological recordings. These findings provide a novel mechanism for early synapse formation that shapes connectivity and functioning of hippocampal neurons.

cell biology↗

bioRxiv2019

SIPA1L2 controls trafficking and signaling of TrkB-containing amphisomes at presynaptic terminals

Amphisomes are transient organelles that derive from fusion of autophagosomes with late endosomes. They rapidly transform into degradative autolysosomes, whereas non-degradative roles of the autophagic pathway have been barely described. Here we show that in neurons BDNF/TrkB receptor bearing Rab7 / Light chain 3 (LC3) - positive amphisomes signal at presynaptic boutons during retrograde trafficking to the soma. Local signaling and inward transport essentially require the Rap GTPase-activating (RapGAP) protein SIPA1L2, which directly binds to TrkB and Snapin to connect TrkB-containing amphisomes to dynein. Association with LC3 regulates the RapGAP activity of SIPA1L2 and thereby retrograde trafficking. Following induction of presynaptic plasticity amphisomes dissociate from dynein at boutons, and this enables local signaling and promotes transmitter release. Accordingly, sipa1l2 knockout mice show impaired BDNF-dependent presynaptic plasticity. Collectively, the data suggest that TrkB-signaling endosomes are in fact amphisomes that during retrograde transport have local signaling capacity in the context of presynaptic plasticity.

neuroscience↗

bioRxiv2018

TRPV4 interacts with mitochondrial proteins and acts as a mitochondrial structure-function regulator

TRPV4 has been linked with the development of sensory defects, neuropathic pain, neurodegenerative disorders such as Charcot Marie Tooth disease and various muscular dystrophies. In all these cases mitochondrial abnormalities were tagged as cellular hallmarks and such abnormalities have been reported as key factor for the pathophysiological conditions. Mitochondria also have the unique ability to sense and regulate their own temperature. Here, we demonstrate that TRPV4, a thermosensitive ion channels, localizes to a subpopulation of mitochondria in various cell lines, in primary cells and also in sperm cells. Improper expression and/or function of TRPV4 induce several mitochondrial abnormalities such as low oxidative potential, high Ca2+-influx and changes in electron transport chain functions. TRPV4 is also involved in regulation of mitochondrial morphology, smoothness, and fusion-fission events. The C-terminal cytoplasmic region of TRPV4 can localize it to mitochondria and interacts with mitochondrial proteins including Hsp60, Mfn1 and Mfn2. Regulation of mitochondria by TRPV4 may contribute to previously uncharacterized mitochondria-specific functions observed in various cell types. This discovery may help to link TRPV4-mediated channelopathies with mitochondria-mediated diseases.

cell biology↗