Biology subjects

Kittel-Schneider, S.

Publications and source records attributed to Kittel-Schneider, S..

5 recordsLinked to original sources

bioRxiv2025

Expression profile of the ADHD risk gene ADGRL3 during human neurodevelopment and the effects of genetic variation

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, affecting [~]5.3 % children, with symptoms including hyperactivity, inattention and impulsivity. Moreover, ADHD persists into adulthood in [~]50 % cases, significantly affecting quality of life. Currently, the complex aetiology of ADHD remains unclear, although it has been shown that it is a highly heritable disorder. Single nucleotide polymorphisms (SNPs) in the adhesion G protein-coupled receptor isoform L3 gene (ADGRL3/ LPHN3) have been consistently associated with ADHD development, symptom severity and treatment response, with the rs1397547 SNP previously shown associated with altered ADGRL3 transcription. Animal models have revealed an essential role of ADGRL3 in glutamatergic synapse development. However, ADGRL3 function has not been investigated in humans. We used human induced pluripotent stem cell (hiPSC)-derived cortical neurons to characterise ADGRL3 expression during human neurogenesis in vitro, and found that expression peaks early in neurodevelopment, consistent with in vivo data. ADGRL3 protein was found primarily expressed in glutamatergic neurons, and localised to growth cone-like structures, supporting a role in neurite outgrowth and glutamatergic synapse development. Lastly, using hiPSC-derived cortical neurons from healthy controls and ADHD patients, we investigated whether the rs1397547 SNP could affect ADGRL3 expression in cortical neurons. We found the rs1397547 SNP was associated with significantly increased ADGRL3 transcription in early neurodevelopmental stages. Moreover, single-cell RNA sequencing of maturing cortical neurons revealed a unique transcriptional profile in SNP carriers. Our results further implicate ADGRL3 in ADHD development and suggest that genetic variation may result in dysregulated glutamatergic neuron development.

neuroscience↗

bioRxiv2024

Impaired Visuospatial Working Memory but Preserved Attentional Control in Bipolar Disorder

BACKGROUNDPersistent deficits in working memory (WM) and attention have considerable clinical and functional impact in people with bipolar disorder (PBD). Understanding the neurocognitive underpinnings of these interacting cognitive constructs might facilitate the discovery of more effective pro-cognitive interventions. Therefore, we employed a paradigm designed for jointly studying attentional control and WM encoding. METHODSWe used a visuospatial change-detection task using four Gabor Patches with differing orientations in 63 euthymic PBD and 76 healthy controls (HCS), which investigated attentional competition during WM encoding. To manipulate bottom-up attention using stimulus salience, two Gabor patches flickered, which were designated as either targets or distractors. To manipulate top-down attention, the Gabor patches were preceded by either a predictive or a non-predictive cue for the target locations. RESULTSAcross all task conditions, PBD stored significantly less information in visual WM than HCS (significant effect of group). However, we observed no significant group by salience or group by cue interactions. This indicates that impaired WM was not caused by deficits in attentional control. CONCLUSIONSOur results imply that while WM is disturbed in PBD, attentional prioritization of salient targets and distractors as well as the utilization of external top-down cues were not compromised. Consequently, the control of attentional selection appears be intact. These findings provide important constraints for models of WM dysfunction in PBD by indicating that later stages of WM encoding are likely primarily impaired. We also demonstrate that selective attention is not among the main sources of cognitive impairment in PBD.

neuroscience↗

bioRxiv2020

Brunner syndrome associated MAOA dysfunction in human dopaminergic neurons results in NMDAR hyperfunction and increased network activity.

BackgroundMonoamine neurotransmitter abundance affects motor control, emotion, and cognitive function and is regulated by monoamine oxidases. Amongst these, monoamine oxidase A (MAOA) catalyzes the degradation of dopamine, norepinephrine, and serotonin into their inactive metabolites. Loss-of-function mutations in the X-linked MAOA gene cause Brunner syndrome, which is characterized by various forms of impulsivity, maladaptive externalizing behavior, and mild intellectual disability. Impaired MAOA activity in individuals with Brunner syndrome results in bioamine aberration, but it is currently unknown how this affects neuronal function. MethodsWe generated human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons from three individuals with Brunner syndrome carrying different mutations, and used CRISPR/Cas9 mediated homologous recombination to rescue MAOA function. We used these lines to characterize morphological and functional properties of DA neuronal cultures at the single cell and neuronal network level in vitro. ResultsBrunner syndrome DA neurons showed reduced synaptic density but hyperactive network activity. Intrinsic functional properties and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission were not affected by MAOA dysfunction. Instead, we show that the neuronal network hyperactivity is mediated by upregulation of the GRIN2A and GRIN2B subunits of the N-methyl-D-aspartate receptor (NMDAR), and rescue of MAOA results in normalization of NMDAR function as well as restoration of network activity. ConclusionsOur data suggest that MAOA dysfunction in Brunner syndrome increases activity of dopaminergic neurons through upregulation of NMDAR function, which may contribute to Brunner syndrome associated phenotypes.

neuroscience↗

bioRxiv2019

Brunner syndrome associated MAOA dysfunction in human iPSC derived dopaminergic neurons results in dysregulated NMDAR expression and increased network activity

Monoamine oxidase A (MAOA) is an enzyme that catalyzes the degradation of dopamine, noradrenaline, and serotonin. Regulation of monoamine neurotransmitter abundance through MAOA activity strongly affects motor control, emotion, and cognitive function. Mutations in MAOA cause Brunner Syndrome, which is characterized by impulsive aggressive behavior and mild intellectual disability (ID). The impaired MAOA activity in Brunner Syndrome patients results in bioamine aberration, but it is currently unknown how this affects neuronal function. MAOA is highly expressed in serotonergic and dopaminergic neurons, and dysfunction of both neurotransmission systems is associated with aggressive behavior in mice and humans. Research has so far mainly focused on the serotonergic system. Here, we generated human induced pluripotent stem cell-derived induced dopaminergic neurons (iDANs) from individuals with known MAOA mutations, to investigate MAOA-dependent effects on dopamine neuronal function in the context of Brunner Syndrome. We assessed iDAN lines from three patients and combined data from morphological analysis, gene expression, single-cell electrophysiology, and network analysis using micro-electrode arrays (MEAs). We observed mutation-dependent functional effects as well as overlapping changes in iDAN morphology. The most striking effect was a clear increase in N-methyl-D-aspartate (NMDA) receptor mRNA expression in all patient lines. A marked increase was also seen in coordinated network activity (network bursts) on the MEA in all patient lines, while single-cell intrinsic properties and spontaneous excitatory postsynaptic currents activity appeared normal. Together, our data indicate that dysfunction of MAOA leads to increased coordinated network activity in iDANs, possibly caused by increased synaptic NMDA receptor expression.

neuroscience↗

bioRxiv2019

Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

genetics↗