Biology subjects

Fendt, M.

Publications and source records attributed to Fendt, M..

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↗

bioRxiv2026

Ferulic acid eicosyl ester enhances cognitive flexibility and modulates arousal-related neural circuits in mice

Cognitive deficits are a major contributor to disability in numerous neuropsychiatric and neurodegenerative disorders, yet effective pharmacological treatments remain limited. Ferulic acid eicosyl ester (FAE-20), a natural constituent of the plant Rhodiola rosea, has previously been identified as an enhancer of simple forms of Pavlovian conditioning in flies, bees, and mice. Here, we investigated whether FAE-20 has further potential to enhance cognitive flexibility, working memory, or spatial learning in mice, and explored potential neurobiological mechanisms underlying such enhancement. Cognitive flexibility was assessed using the attentional set-shifting task (ASST). Subchronic FAE-20 treatment significantly improved ASST performance in both male and female young adult mice, indicating enhanced cognitive flexibility. In contrast, no effects were observed on spatial working memory, assessed by spontaneous alternations in the Y-maze, or on spatial learning in the Barnes maze in either young or aged mice. Notably, FAE-20 enabled spatial learning in the Barnes maze in a subgroup of aged mice that failed to learn the task under vehicle treatment. Histological analyses using c-Fos immunohistochemistry as a marker of neural activity and doublecortin expression and spine density as markers of hippocampal plasticity revealed sex-specific effects on components of the ascending arousal system. FAE-20 increased the activation of orexinergic neurons in the lateral hypothalamus of male mice, whereas it reduced the activity of cholinergic neurons in the laterodorsal tegmental nucleus of females. No effects were detected on hippocampal neurogenesis or dendritic spine density. These findings suggest that the cognitive effects of FAE-20 are selective, depending on the cognitive demands of the task and the baseline cognitive abilities of the animals, and may be mediated, at least in part, by modulation of arousal-related neural circuits. HighlightsO_LIFAE-20 enhanced cognitive flexibility in young adult mice C_LIO_LIEffects of FAE-20 were strongest in demanding cognitive tasks C_LIO_LIAged poor learners benefited from FAE-20 treatment C_LIO_LIFAE-20 activated hypothalamic orexin neurons in male mice C_LIO_LIFAE-20 modulated ascending arousal systems in a sex-specific manner C_LI

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

Short Polysialic Acid Counteracts Age-Related Synaptic and Cognitive Deficits

Impaired activity of glutamate transporters, elevated concentration of extrasynaptic glutamate and hyperactivity of extrasynaptic GluN2B-containing NMDA receptors are common features in aging and several neurological conditions, including Alzheimers disease (AD). Previous studies revealed that polysialic acid (polySia), a glycan predominantly carried by the neural cell adhesion molecule NCAM, inhibits extrasynaptic NMDA receptors and supports synaptic plasticity in healthy adult brains. Moreover, intranasal delivery of polySia with the degree of polymerization 12 (NANA12) rescued synaptic plasticity and cognitive functions in models of tauopathy and amyloidosis associated with AD. Here, we comparatively studied the effects of NANA12 in young (4 months) old (26 months) and very old (29 months) mice. Strikingly, NANA12 promoted cognitive flexibility in attentional set-shifting (ASST) tests and spatial memory in the Barnes maze in very old mice. To capture fine-grained effects undetectable by conventional methods, we introduced a novel trial-wise data analysis approach for evaluating ASST performance. The observed cognitive improvements were not due to changes in the size of hippocampal memory engrams, visualized by c-Fos immunolabeling after reactivation of spatial memory in the probe trial. Five-day treatment with NANA12 did not affect neuronal structure (MAP2 levels), expression of senescence (lipofuscin) or neuroinflammation (microglial Iba1) markers, activation of BDNF receptors (p-TrkB) or expression of endogenous polySia in the hippocampus of very old mice. However, cognitive improvements correlated with the normalized size of CD68+ microglial lysosomes and reduced amounts of pre- and postsynaptic proteins at these structures. Thus, our data demonstrate the potential of short polySia to reduce synaptic phagocytosis and restore key cognitive functions attenuated in aging.

neuroscience↗