A5046921787- Neurotransmitter Receptor Influence on Behavior
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Parkinson's Disease Mechanisms and Treatments
- Neural dynamics and brain function
- Advanced Fluorescence Microscopy Techniques
- Genetics and Neurodevelopmental Disorders
- Neurological disorders and treatments
- Functional Brain Connectivity Studies
- Cellular transport and secretion
- Zebrafish Biomedical Research Applications
- Neuroscience and Neural Engineering
- Autism Spectrum Disorder Research
- Nerve injury and regeneration
- Bipolar Disorder and Treatment
- Attention Deficit Hyperactivity Disorder
- DNA and Nucleic Acid Chemistry
- Particle Detector Development and Performance
- Drug Transport and Resistance Mechanisms
- Particle physics theoretical and experimental studies
- Lipid Membrane Structure and Behavior
- Advanced Electron Microscopy Techniques and Applications
- Advanced NMR Techniques and Applications
- Nuclear Receptors and Signaling
- Force Microscopy Techniques and Applications
University of Copenhagen
2015-2025
Maersk (Denmark)
2018-2025
Mental Health Services
2023
Lundbeck Foundation
2013-2023
Laboratory of Molecular Genetics
2021
Université de Montréal
2021
Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort patients with atypical movement identified 2 DAT coding variants, DAT-Ile312Phe presumed de novo mutant DAT-Asp421Asn, in an adult male early-onset parkinsonism ADHD. According single-photon...
The precise regulation of synaptic dopamine (DA) content by the DA transporter (DAT) ensures phasic nature signal, which underlies ability to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions system are implicated in a number neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, autism spectrum (ASD). An ASD-associated de novo mutation SLC6A3 gene resulting threonine-to-methionine...
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine (DA) neurons in substantia nigra pars compacta (SNc). Rare genetic mutations genes such as Parkin, Pink1, DJ-1, α-synuclein, LRRK2 and GBA are found to be responsible for about 15% cases. A key unanswered question PD pathophysiology why would these mutations, impacting basic cellular processes mitochondrial function neurotransmission, lead selective degeneration SNc DA neurons? We previously showed...
Abstract Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across plasma membrane in various tissues throughout human body. OCT3 plays a key role low-affinity, high-capacity uptake monoamines most including heart, brain liver. Its deregulation diseases. Despite its importance, structural basis function inhibition has remained enigmatic. Here we describe cryo-EM structure at 3.2 Å resolution. Structures bound to two inhibitors,...
The dorsal (DS) and ventral striatum (VS) receive dopaminergic projections that control motor functions reward-related behavior. It remains poorly understood how dopamine release dynamics across different temporal scales in these regions are coupled to behavioral outcomes. Here, we employ the sensor dLight1.3b together with multiregion fiber photometry machine learning-based analysis decode during self-paced exploratory behavior mice. Our data show a striking coordination of rapidly...
Dopamine regulates reward, cognition, and locomotor functions. By mediating rapid reuptake of extracellular dopamine, the dopamine transporter is critical for spatiotemporal control dopaminergic neurotransmission. Here, we use super-resolution imaging to show that dynamically sequestrated into cholesterol-dependent nanodomains in plasma membrane presynaptic varicosities neuronal projections neurons. Stochastic optical reconstruction microscopy reveals irregular (∼70 nm mean diameter) were...
Genetic factors are known to significantly contribute the etiology of psychiatric diseases such as attention deficit hyperactivity disorder (ADHD) and autism spectrum bipolar disorders, but underlying molecular processes remain largely elusive. The dopamine transporter (DAT) has received continuous a potential risk factor for disease, it is critical homeostasis serves principal target ADHD medications. Constrain metrics DAT-encoding gene, solute carrier family 6 member 3 (SLC6A3), indicate...
Abstract Dopamine supports locomotor control and higher brain functions such as motivation learning. Consistently, dopaminergic dysfunction is involved in a spectrum of neurological neuropsychiatric diseases. Detailed data on dopamine dynamics needed to understand how signals translate into cellular behavioral responses, uncover pathological disturbances dopamine-related Genetically encoded fluorescent sensors have recently enabled unprecedented monitoring vivo. However, these sensors’...
Chemical neurotransmission typically occurs through synapses. Previous ultrastructural examinations of monoamine neuron axon terminals often failed to identify a pre- and postsynaptic coupling, leading the concept "volume" transmission. Whether this results from intrinsic properties these neurons remains undefined. We find that dopaminergic in vitro establish distinctive axonal arbor compared glutamatergic or GABAergic both size propensity avoid direct contact with target neurons. While most...
The nanoscopic organization and regulation of individual molecular components in presynaptic varicosities neurons releasing modulatory volume neurotransmitters like dopamine (DA) remain largely elusive. Here we show, by application several super-resolution microscopy techniques to cultured mouse striatal slices, that the DA transporter (DAT), a key protein dopaminergic neurons, exists membrane dynamic equilibrium between an inward-facing nanodomain-localized outward-facing unclustered...
Striatal dopamine (DA) release regulates reward-related learning and behavioural activation is believed to consist of a short-lived phasic continuous tonic component. Here, we build three-dimensional model extracellular DA dynamics in dorsal (DS) ventral striatum (VS) that include tens thousands sites. The predicts rapid DS with little-to-no basal DA, much slower the VS enabling build-up level. These regional differences do not primarily reflect different phenomena but rather arise from...
Striatal dopamine (DA) release regulates reward-related learning and behavioural activation is believed to consist of a short-lived phasic continuous tonic component. Here, we build three-dimensional model extracellular DA dynamics in dorsal (DS) ventral striatum (VS) that include tens thousands sites. The predicts rapid DS with little-to-no basal DA, much slower the VS enabling build-up level. These regional differences do not primarily reflect different phenomena but rather arise from...
Amphetamines (AMPHs) are substrates of the dopamine transporter (DAT) and reverse direction (DA) transport. This has been suggested to depend on activation Ca2+-dependent pathways, but mechanism underlying transport via endogenously expressed DAT is still unclear. Here, enable concurrent visualization by live imaging extracellular DA dynamics cytosolic Ca2+ levels, we employ fluorescent sensor jRGECO1a in cultured dopaminergic neurons together with GRABDA1H cocultured "sniffer" cells. In...
Dysfunctional dopaminergic neurotransmission is central to movement disorders and mental diseases. The dopamine transporter (DAT) regulates extracellular levels, but the genetic mechanistic link between DAT function dopamine-related pathologies not clear. Particularly, pathophysiological significance of monoallelic missense mutations in unknown. Here, we use clinical information, neuroimaging, large-scale exome-sequencing data uncover occurrence phenotypic spectrum a coding variant,...
Abstract Dual-color single-molecule localization microscopy (SMLM) provides unprecedented possibilities for detailed studies of colocalization different molecular species in a cell. However, the informational richness data is not fully exploited by current analysis tools that often reduce to single value. Here, we describe tool specifically designed determination co-localization both 2D and 3D from SMLM data. The approach uses function describes relative enrichment one on density...
Abstract Midbrain dopaminergic ( DA ergic) neurons are a heterogeneous cell group, composed of functionally distinct populations projecting to the basal ganglia, prefrontal cortex and limbic system. Despite their functional significance, midbrain population ergic is sparse, constituting only 20 000–30 000 in mice, development novel tools identify these cells warranted. Here, bacterial artificial chromosome mouse line [ Dat1 ‐enhanced green fluorescent protein eGFP )] from Gene Expression...
Abstract While the physiological function and mechanisms of agonist‐dependent G protein‐coupled receptor (GPCR) internalization have been extensively studied, functional characterization constitutive these critically important receptors has received less attention. Here we relate more than 30 therapeutically targeted GPCRs to their agonist‐induced internalization. The ranges from levels bulk membrane endocytosis in some cases for other receptors. Moreover, with high this occludes further...
The dopamine (DA) transporter (DAT) is part of a presynaptic multiprotein network involving interactions with scaffold proteins via its C-terminal PDZ domain-binding sequence. Using mouse model expressing DAT mutated PDZ-binding sequence (DAT-AAA), we previously demonstrated the importance this binding for striatal expression DAT. Here, show by application direct stochastic reconstruction microscopy not only that level reduced in DAT-AAA mice but also nanoscale distribution altered higher...
ABSTRACT Chemical neurotransmission in the brain typically occurs through synapses, which are structurally and functionally defined as sites of close apposition between an axon terminal a postsynaptic domain. Ultrastructural examinations terminals established by monoamine neurons often failed to identify similar tight pre- coupling, giving rise concept “diffuse” or “volume” transmission. Whether this results from intrinsic properties such modulatory remains undefined. Using efficient...
SUMMARY The nanoscopic organization and regulation of individual molecular components in presynaptic varicosities neurons releasing modulatory volume neurotransmitters like dopamine (DA) remain largely elusive. Here we show by application several super-resolution microscopy techniques to cultured mouse striatal slices, that the transporter (DAT), a key protein dopaminergic neurons, exists membrane dynamic equilibrium between an inward-facing nanodomain-localized outward-facing unclustered...
<title>Abstract</title> Missense mutations of PARK20/SYNJ1 (synaptojanin1/Synj1) have been linked to complex forms familial parkinsonism, however, the molecular and cellular changes associated with dopaminergic dysfunction remains unknown. We now report fast depletion evoked dopamine (DA) altered maintenance axonal transporter (DAT) in Synj1+/- neurons. While Synj1 has traditionally known facilitate endocytosis synaptic vesicles, we demonstrated that axons cultured neurons exhibit an...