Biology subjects

Montenegro-Venegas, C.

Publications and source records attributed to Montenegro-Venegas, C..

6 recordsLinked to original sources

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↗

bioRxiv2025

Amphisome biogenesis couples synaptic autophagy to local protein synthesis

Synaptic neurotransmission imposes high demands on membrane turnover, metabolism, and the remodeling of presynaptic molecular composition. While the impact of autophagy on neurotransmission has been firmly established, evidence for activity-dependent synaptic induction of autophagy remains surprisingly limited. Here, we demonstrate that amphisomes containing BDNF/TrkB are formed at presynaptic boutons following sustained synaptic activation. Activity-dependent bulk endocytosis serves as a membrane source for amphisome biogenesis, while key autophagy proteins are recruited to the active zone, and autophagy initiation is triggered locally by the energy-sensing kinase AMPK. BDNF/TrkB-containing amphisomes contribute to the turnover of key presynaptic cytoskeletal proteins involved in synaptic vesicle clustering. The formation of amphisomes following sustained synaptic activity facilitates both the degradation of these proteins and their replenishment through local translation of their mRNAs at presynaptic boutons. We propose that activity-induced synaptic autophagy largely reflects amphisome formation, which in turn is required for the replacement of proteins within the local presynaptic cytomatrix.

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↗

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↗