Biology subjects

Annamneedi, A.

Publications and source records attributed to Annamneedi, A..

6 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

In silico analysis of the altered protein structure and functions caused by existing synaptic gene mutations in Indian population having neurological disorders

Neurological disorders encompass a diverse range of conditions that affect individuals cognitive, emotional, and social functioning. Though these disorders are multifactorial, genetic factors play a significant role in the pathogenesis. Especially, synaptic gene mutations or synaptic protein dysfunction are shown to be closely associated with neuropathology. This study aims at understanding the critical role of synaptic compartment by conducting comprehensive analysis of existing synaptic gene mutations responsible for the development of three significant disorders in the Indian population: autism spectrum disorder (ASD), epilepsy and schizophrenia (SZ). Our in-silico analysis predicts that mutations in synaptic genes RPL10 (rs387906727), GABRA1 (rs121434579) and DRD2 (rs1801028) corresponding to ASD, epilepsy and SZ respectively, are deleterious. Of these, SZ-related mutations in DRD2 (D(2) dopamine receptor) are deleterious and due to its genetic association also with ASD as well sociosexual behavior, this study focuses on DRD2. In silico analysis using molecular docking revealed an abnormal interaction between D(2) dopamine receptor and neuronal calcium sensor 1, which may hamper neurotransmitter regulation. We further employed a post-weaning social isolation mice model of SZ to investigate the D(2) dopamine receptor expression levels in hippocampus and social behavioral changes. We observed a reduced immunofluorescent intensities of D(2) dopamine receptor and NCS1 compared to group-housed controls in hippocampus and a trend towards an impaired sociosexual behavior characterized by anogenital sniffing in a male-female social interaction test. Altogether, our study helps to further our understanding of synaptic signaling in the context of SZ and decode the probable mechanism by which disrupted synaptic signaling and protein-protein interaction may lead to the disease pathology and further aid in identifying novel therapeutic targets.

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↗