Biology subjects

Schmeisser, M. J.

Publications and source records attributed to Schmeisser, M. J..

8 recordsLinked to original sources

bioRxiv2026

Consequences of sustained modulation of VIP-expressing neurons in mouse corticolimbic regions on anxiety-related avoidance behaviors, social functioning, and associative fear learning

GABAergic inhibitory neurons play a central role in shaping network dynamics, and accordingly, their dysfunction is implicated in the pathophysiology of various psychiatric, neurodevelopmental, and neurological disorders. In the past decade, studies on vasoactive intestinal polypeptide-expressing inhibitory neurons (VIP+ neurons) have positioned them as critical components of this circuitry. In particular, VIP+ neurons have been proposed to function within a canonical disinhibitory circuit motif, preferentially inhibiting other interneuron subtypes, to ultimately modulate the gain and activity of local pyramidal neurons. However, their contribution to psychiatrically relevant behavioral endophenotypes is still not fully understood, limiting our ability to target these neurons for therapeutic purposes. In the present study, we systematically assessed the functional contribution of VIP+ neurons to affective and social behaviors. To this end, we used a chemogenetic approach to manipulate the activity of VIP+ neurons in core corticolimbic regions, including the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC). The consequences of either activating or inhibiting VIP+ neurons in these regions were observed while mice underwent a battery of behavioral tasks assessing anxiety-related avoidance behaviors, social interest and recognition, and associative fear learning. While sustained modulation of VIP+ neurons had no significant effect on anxiety-related or social behaviors in any of the brain regions assessed, it produced a robust reduction in associative fear learning specifically in the mPFC. These findings demonstrate that the consequences of sustained VIP+ neuron modulation depend on both anatomical location and behavioural context. Moreover, they identify VIP+ neurons in the mPFC as potentially clinically relevant targets for interventions aimed at modulating fear-related circuits.

neuroscience↗

bioRxiv2026

Single shot low-dose radiation durably and focally increases cortical excitability: a potential therapy for neuronal circuit disorders?

Herein, we assess the potential of low-dose stereotactic radiosurgery (SRS) to modulate neuronal network states without apparent damage to cellular integrity. Using a small animal radiation research platform (SARRP), a 1 mm3 focal target in the mouse visual cortex was irradiated with doses of 5, 20, and 40 Gy. One-month later a significant dose-dependent increase in excitatory synapse numbers was observed, notably limited to the treated visual cortex and not the adjacent somatosensory cortex. Six months post-irradiation, cortical neuronal microcircuit activity was monitored in awake mice using high sensitivity two-photon calcium imaging. A single 5 Gy dose resulted in a significant microcircuit-wide increase of spontaneous neuronal activity, consistent with a lasting shift in the functional architecture of the irradiated nodal network. At higher SRS doses (40 Gy) this neuromodulatory window appears to close. In aggregate, these data suggest that low-dose radiation could, in some circumstances, be exploited by selected high precision SRS technologies to durably modulate neuronal circuit disorders. Some, or even all the clinical benefits reported in the companion article by Zhao et al. are likely attributable to the biological properties we sought to characterize in our research.

neuroscience↗

bioRxiv2026

Performance-impacting brain state maladaptation driving disease progression in early mouse and human neuroinflammation

The neuronal mechanisms driving progression in neuroinflammatory disorders from early relapse-remitting phases to later neurodegenerative phases remain largely elusive. Functional brain state shifts towards hyperactivity, persisting beyond relapses, represent an early maladaptive response. Here, in remission stage of an experimental autoimmune encephalitis (EAE) mouse model of RRMS, we identified a reduced excitability upon optogenetic stimulation in the brain stem, the area of active disease, while in the cortex a persistent cortical neuronal hyperactivity and synaptic remodeling emerged, accompanied with an increase of markers of early apoptosis. In contrast, hippocampal circuits, which undergo a functional state shift without hyperactivity, do not show increased apoptosis. Visual cortical networks showed a deterioration of the accuracy of encoding visual information and a decrease in the behavioural visual discrimination ability in mice. In RRMS patients in remission, we identified a reduced visual colour discrimination, indicating both the presence and the clinical relevance of early brain state maladaptation that may contribute to progression independent from relapse activity (PIRA). SummaryIn a RRMS model and in patients, impaired visual processing was reported, indicating brain state maladaptations, associated with persistent cortical hyperactivity, brain stem hypoactivity, synaptic remodeling, and apoptosis. These maladaptations might contribute to relapse-independent disease progression through sustained network dysfunction.

neuroscience↗

bioRxiv2026

Selective Shank3 Deletion in Glutamatergic Neurons of the Anterior Insular Cortex Induces Autism-Related Behavior and Circuit Dysfunction

Mutations in the synaptic scaffold protein SHANK3 represent one of the most frequent genetic causes of autism spectrum disorder (ASD), yet the circuit mechanisms through which SHANK3 dysfunction leads to behavioral alterations remain incompletely understood. The anterior insular cortex (aINS) is a key integrative hub involved in socio-emotional processing, anxiety regulation, and social cognition, a group of behaviors frequently disrupted in ASD. Here, we investigated whether selective deletion of SHANK3 signaling in glutamatergic neurons of the aINS is sufficient to produce ASD-relevant behavioral and circuit phenotypes. Using conditional Shank3flox4-22 mice combined with stereotaxic viral delivery of Cre recombinase under the CaMKII promoter, we selectively deleted Shank3 in glutamatergic neurons of the aINS. Behavioral phenotyping revealed increased anxiety-like behavior, enhanced repetitive behavior, and impaired social memory, while sociability and locomotor activity were largely preserved. These behavioral alterations were accompanied by genotype-dependent differences in neuronal activity revealed by calcium imaging, indicating disrupted activity dynamics in insular glutamatergic neurons following Shank3 deletion. To assess the broader relevance of these findings, we evaluated the behavioral profile of BTBR T+ Itpr3tf/J mice, a model of idiopathic ASD, in the same battery of behavioral tests. Several behavioral alterations observed following insular Shank3 deletion partially overlapped with those present in BTBR mice, supporting the relevance of aINS Shank3 in ASD-related phenotypes. Together, these findings identify glutamatergic neurons of the aINS as a critical locus through which Shank3 dysfunction can disrupt socio-emotional, cognitive, and repetitive behaviors. Our results highlight the aINS as a key circuit node contributing to ASD-related behavioral alterations and provide mechanistic insight into how synaptic scaffold disruption leads to circuit dysfunction and produces behavioral alterations.

neuroscience↗

bioRxiv2026

Anterior insular CB1 receptor signaling selectively regulates social novelty and anxiety-related behaviors

Several neurodevelopmental disorders (NDDs) are characterized by impairments in social behavior and affective dysregulation. Converging evidence implicates the endocannabinoid system in the control of both behaviors. However, the brain region-specific contribution of cannabinoid receptor type 1 (CB1R) signaling to these NDD-relevant phenotypes remains unclear. The anterior insular cortex (aINS) is a key integrative hub involved in socio-emotional processing and social novelty recognition. Whether CB1Rs within this region are sufficient to regulate behavioral domains disrupted in NDDs remains unclear. Here, we employed a Cre-dependent viral strategy to selectively restore CB1R mRNA expression in the aINS of global CB1R-deficient mice. Region-specific rescue of CB1R in the aINS normalized social novelty discrimination and reduced anxiety-like behavior as compared to mice lacking CB1R, while leaving basal sociability and locomotor activity unaffected. In addition, insular CB1R re-expression modulated repetitive-like behaviors without broadly altering other behavioral domains. These effects were observed in the absence of off-target expression, supporting the specificity of the genetic manipulation. Our findings demonstrate that CB1R mRNA expression within the aINS is sufficient to regulate distinct socio-emotional and repetitive behavioral domains. These results identify the aINS as a critical CB1-dependent modulatory node and provide mechanistic insight into how region-specific endocannabinoid signaling contributes to behavioral phenotypes relevant to NDDs.

neuroscience↗

bioRxiv2024

Glucocorticoids target postnatal oligodendrocyte precursor cells to modulate adult hippocampal network plasticity and stress-induced behavior

Glucocorticoid receptors (GRs) are key mediators of how the stress hormone glucocorticoids (GCs) shape postnatal brain development and adaptive plasticity. Because GC signaling is critical during this period, postnatal GC concentrations are tightly regulated in the brain, whereas excessive levels of circulating GCs can disrupt developmental trajectories and increase the risk of psychiatric disorders later in life. GR function influences multiple neural cell types, but its cell-specific roles, particularly early in development, remain poorly understood. Oligodendrocyte precursor cells (OPCs), which generate myelinating oligodendrocytes and actively modulate neuronal networks, express GRs and can therefore respond to fluctuations in GC levels. Although excessive GC exposure during early life adversity has been linked to changes in OPC development, the physiological role of GR signaling specifically within OPCs remains unclear. To address this, we conditionally deleted GRs in postnatal OPCs in mice to investigate the role of physiological GC signaling in OPC proliferation and maturation, as well as in neuronal network activity and behavior. This deletion resulted in reduced oligodendrocyte and myelinated axon density in the hippocampus, sex-specific alterations in hippocampal activity and long-term potentiation following acute challenge, and impairments in memory formation in adulthood. Our findings reveal a novel, OPC-specific role for GRs and suggest that physiological GR activity in the oligodendrocyte lineage contributes to normal hippocampal plasticity, learning and memory. Significance StatementGlucocorticoid receptors (GRs) mediate the effects of the stress hormone glucocorticoids (GCs) on postnatal brain development and adaptive plasticity. While the function of GRs in neurons is well characterized, much less is known about their role in oligodendrocyte precursor cells (OPCs). OPCs, which give rise to myelinating oligodendrocytes and participate in the modulation of neuronal networks, express GRs and can therefore sense fluctuations in GCs during stress response; however, the physiological role of GRs in OPCs remains unclear. In this study, we found that deleting GRs in early postnatal OPCs reduced the density of oligodendrocytes and of myelinated axons, altered hippocampal activity and long-term potentiation in response to acute challenge, and impaired memory formation in adult mice. These findings identify OPCs as key targets of GR signaling and suggest that physiological receptor activity in the oligodendrocyte lineage contributes to normal hippocampal plasticity, learning, and memory.

neuroscience↗

bioRxiv2022

Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation

AO_SCPLOWBSTRACTC_SCPLOWThe function of GABAergic synapses is critically shaped by cell adhesion proteins that recruit GABAARs to synapses and mediate transsynaptic signalling, but the synapse-type-specific function of such synaptic adhesion proteins and their mutual interaction remain incompletely understood. A ubiquitous cell adhesion protein at GABAergic synapses is Neuroligin-2 (Nlgn2), which recruits synaptic GABAARs by promoting the assembly of the postsynaptic gephyrin scaffold. While Nlgn2 is present at virtually all GABAergic synapses throughout the forebrain, its loss affects different GABAergic synapse subtypes with different severity, indicating that synapse-specific interactors and synapse-organizer-redundancies define the function of Nlgn2 for a given synapse type. Here we investigated how Nlgn2 function at GABAergic synapses in mouse hippocampal area CA1 is modulated by two recently identified interaction partners, MDGA1 and MDGA2. We show that Nlgn2 and MDGA1 colocalize most prominently in the stratum radiatum (S.R.) of area CA1, and that combined Nlgn2 and MDGA1 deletion causes a layer-specific exacerbation of the loss of gephyrin puncta in layer S.R. seen following Nlgn2 deletion. Intriguingly, combined Nlgn2 and MDGA1 deletion concurrently ameliorates the abnormal cytosolic gephyrin aggregation, the reduction in inhibitory synaptic transmission and the exacerbated anxiety-related behavior seen in Nlgn2 knockout (KO) mice. In contrast, heterozygous deletion of MDGA2 in Nlgn2 KO mice has only minor effects on gephyrin and GABAAR puncta and does not normalize cytosolic gephyrin aggregates, inhibitory synaptic transmission or anxiety-related behavior. Our data indicate that MDGA1, but not MDGA2, modulates Nlgn2 function, primarily by regulating the formation of cytosolic gephyrin aggregates. Given that both Nlgn2 and the MDGA family of proteins have been linked to psychiatric disorders, such as autism and schizophrenia, our data lead to the notion that abnormal gephyrin aggregation may contribute to the pathophysiology of these disorders, and that intervention with gephyrin aggregation could present a novel therapeutic strategy.

neuroscience↗

bioRxiv2021

NECAB2 orchestrates an endosomal pathway of mitochondrial quality control at striatal synapses

Synaptic signaling depends on ATP generated by mitochondria. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction and thus requires efficient mitochondrial quality control and repair. We found that global knockout of the neuronal calcium-binding protein 2 (NECAB2) in the mouse causes loss of striatal synapses and behavioral phenotypes related to striatal dysfunction such as reduced motivation and altered sensory gating. Striatal mitochondria from Necab2 knockout mice are more abundant and smaller. They are characterized by increased respiration and superoxide production resulting in oxidative stress. This accumulation of dysfunctional mitochondria is caused by a defective assembly of mitochondria with early endosomes in a pathway that involves the small GTPase Rab5 and its guanine nucleotide exchange factor Alsin/ALS2. NECAB2 therefore participates in an endosomal pathway of mitochondrial stress response and repair important for striatal function.

neuroscience↗