Expertise

During my postdoctoral training in Rouach lab, my research was focused on the role of astrocytes in the pathophysiology of Fragile X syndrome (FXS), a common inherited form of intellectual disability caused by deletion of FMR1 gene and lack of its product fragile X mental retardation protein (FMRP). This project is bringing substantial proof of astrocyte potassium channel Kir4.1 as a major contributor to neuronal hyperexcitability, disturbed extracellular K+ concentration and behavioral abnormalities in KO mouse model of FXS (Bataveljic et al., 2024). Importantly, we provide the first evidence of astrocyte mRNA encoding Kir4.1 channel as a novel binding target of FMRP and further demonstrate diminished expression of this channel in the hippocampus of mice lacking FMRP (Bataveljic et al., 2024). Viral delivery of Kir4.1 channel into astrocytes of KO mice rescued normal astrocyte and neuronal properties as well as behavioral phenotype and thus established Kir4.1 channel as a molecular target in FXS (Bataveljic et al., 2024). Astrocytes are well established source of recycled glutamate as they are responsible for efficient glutamate clearance upon synaptic activity through glutamate transporters expressed in their perisynaptic processes. These glial cells distinctively express glutamine synthetase that helps conversion of glutamate to glutamine. To directly track glutamine transfer in live cells, we developed a fluorescent probe, rhodamine-tagged glutamine molecule in the scope of another project during my postdoc in Rouach team. Our approach led to the identification of activity-dependent glutamine supply from astrocyte network to presynaptic compartment that is mediated by connexin 43 (Cx43) hemichannel (Cheung et al., 2022). In the same study, we uncovered that astroglial glutamine supply via Cx43 hemichannels is required for synaptic activity and recognition memory (Cheung et al., 2022). Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by the death of motor neurons in the brain and the spinal cord. Taking the advantage of SOD1 rat model of ALS, we employed MRI in live animals and identified brain regions of neurodegenerative and neuroinflammatory changes, enlarged lateral ventricles and compromised blood-brain barrier (BBB) (Bataveljic et al., 2009; 2011). BBB stability is largely determined by water and potassium channels highly enriched in astrocyte endfeet ensheathing blood vessels. Main findings of my PhD work supervised by prof. Andjus show increased expression of astrocyte water channel AQP4 and decreased expression of astrocyte potassium channel Kir4.1 in ALS rat brain (Bataveljic et al., 2012; Nicaise et al., 2009). Along with Kir4.1 downregulation, ALS astrocytes exhibit impaired membrane properties and reduced ability to uptake K+ through Kir channels (Bataveljic et al., 2012). We propose that impaired ability of astrocytes to maintain water and potassium homeostasis affects motoneuronal microenvironment causing their dysfunction and death in ALS. Oligodendrocytes have various functions that are governed by the presence of distinct ion channels in their membranes including highly expressed potassium channel Kir4.1. Along with the regulation of extracellular K+, this channel is responsible for the physiological maturation of the oligodendrocytes and actively participates in shaping neuronal activity. Although ALS is a non-demyelinating disease, we demonstrate the presence of dysmorphic oligodendrocytes in the ALS spinal cord that is indicative of a degenerative phenotype (Peric et al., 2021). Moreover, we show that the reduction in the Kir4.1 expression is associated with altered functional properties of ALS oligodendrocytes. These cells display impaired membrane properties and lower Kir currents (Peric et al., 2021). By focusing on the role of oligodendrocytes and astrocytes in ALS, we uncover the disruption of Kir4.1 activity as an important contributor to ALS pathophysiology.

Technique

● Patch-clamp in astrocytes and neurons (acute slices and cell cultures) ● Double recording in acute slices: patch-clamp in astrocyte and fEPSP ● Measurement of extracellular K concentration (ion-sensitive electrode) ● Immunofluorescence ● Confocal and STED microscopy ● Immunoprecipitation ● Surface biotinylation ● Synaptosomes ● Western blot ● FISH ● qPCR & ddPCR ● Brain stereotaxic injections ● Viral-vector based genetic manipulations ● Primary cell cultures ● Rodent transcardial perfusion and tissue fixation ● Rodent care and handling

Users

Researchers in neuroscience or other fields applying similar methodology.

Keywords

-Neuroimaging and neurophysiology expertise in human participants (healthy and patient populations) -Computational modelling of internal representations of knowledge in the human brain - Artificial intelligence for diagnostic use in the Memory Clinic

Technique

-MRI: fMRI, VBM, uni/multivariate analysis, ... -EEG/MEG: ERP, uni/multivariate analysis, ... -Computational models: explicit models of vision and language -Multivariate methods: RSA, SVM, NN, ...

Users

Researchers working with MRI and EMEG data of human participants Cognitive neuroscientists

Keywords

In vivo neuroscience, Neuroinformatics, Neuro mri, Cognitive neurology, Neurocognitive disorders, Artificial intelligence (ai), Neurodegenerative disorders, Computational neuroscience

1) Metabolic and neurochemical analyses 2) Behavioural phenotyping of mouse models and preclinical evaluation of symptomatic and preventive therapeutic interventions in validated transgenic mouse models for Alzheimer's disease 3) Diagnostic reference centre for biomarkers in dementia 4) Scientific consulting 5) Brain banking

Technique

-Apparatus for diagnostic and therapeutic procedures in neurological clinical practice -Neuroimaging apparatus: fMRI, MRS, (neuro-activation) SPECT; Pupil assay lab; Updated databases and available patient populations for virtually all fields of clinical neurology; Neurocognitive test instruments : Middelheim Frontality score (MFS) and Emotional Facial Recognition task (EFRT). -Neuromotor abilities: accelerating Jones-Roberts rotarod for mice, Dunham-Miya rotarod for rats and mice, wire suspension test, gait test, stationary beam task, wire suspension test; -Activity and exploration: open field activity and exploration (incl. social) with computerized video-tracking, dark-light transition box with digital counter, computerized registration of cage activity patterns; -Learning tests: step-through box and small animal shocker for active and passive avoidance training, plus-shaped water maze, Morris water maze with computerized video-tracking for hidden and visible escape training, automated operant conditioning chambers with data acquisition software for reward and punishment conditioning protocols, manual conditioning chamber for contextual fear conditioning; -Analysis of behavioural alterations (anxiety, depression, etc.): forced swim test, tail suspension test, sucrose preference task, holeboard, elevated plusmaze -Apparatus for electrographic and evoked potential recording in rats and mice; Neural cell culture room and equipment

Users

- Clinical neuroscientists - Molecular biologists (a.o. geneticists) - Farmaceutical industry - Metabolic-diagnostic departments

Keywords

Hplc, Biomarkers, Amino acid analysis, Behavioural neuroscience, Biogenic amines analysis

Neuroinformatics, computational modeling en neurophysiology.

Technique

Computer simulation of signal transduction or of cells.

Users

- Biotech sector - Farmaceutical companiers

Keywords

Computational models, Neurophysiology, Neuroinformatics

The overall aim of our group is to understand how neuronal circuits form early in development, as well as the processes that lead to malfunction or degeneration of these circuits later in life. Research is conducted in both humans and other model species using a variety of methods including EEG measurements, in vitro and in vivo electrophysiology, HPLC and other molecular biology techniques. The focus is on the brain areas of the hippocampus, cortex as well as the basal ganglia and their role in cognition and motor control.

Technique

Instrumentation (multi-neuron patch-clamp electrophysiology, interface electrophysiology, multi-electrode arrays, silicon probes) and data processing software for in vitro and in vivo molecular, anatomical and neurophysiological investigations.

Users

Neuroscientists

Keywords

Neurobiology, Electrophysiology

Reference Centre for Biological Markers of Dementia (BIODEM).

Technique

Analyses of biochemical markers in cerebrospinal fluid or plasma (ELISA, Luminex xMAP technology).

Users

- Research laboratories - Referring clinicians

Keywords

Neurology, Neurochemical markers, Alzheimer, Neurochemistry, Dementia, Biomarkers

Electrophysiological analysis and Patch clamp.

Technique

- Electrophysiological analysis - Patch clamp

Users

Pharmaceutical industry.

Keywords

Channel gating, Molecular cell biology of ion channels, Stable cell line generation, Patch-clamp

Animal modelling of disorders with neurological symptomatology Cognitive and behavioral alterations in Alzheimer’s disease and related neurodegenerative disorders Neurochemical and neuropathological correlates of behavioral alterations In-depth phenotyping of rodent models via assessment of various levels of learning and memory , behavioral alterations (e.g. aggression, circadian rhythm changes, anxiety), motor performance, EEG-based sleep or epilepsy studies. Rodent surgery including stereotactic procedures (non)pharmacological interventions with symptomatic or disease-modifying procedures Behavioral and biochemical biomarkers of Alzheimer’s disease in Down syndrome

Technique

- Cognitive and behavioural evaluation in rodents - Pharmacological and non-pharmacological modulation of behavioural alterations - In vivo electrophysiology (sleep, epilepsy) - Neurodegenerative disorders, including Alzheimer's disease and related disorders - Animal models of neurodegenerative disorders - Surgical and stereotaxic techniques in rodents - Neurochemical and neuropathological correlaten of behavioural alterations and brain functions - Neurophysiology and behavioural neurosciences - Laboratory animal techniques including project design, legislative framework, animal welfare and ethical considerations

Users

Researchers requiring in-depth phenotyping and validation of rodent models including neurochemical and neuropathological correlates, pharmacological interventions and surgical procedures

Keywords

Dementia, Behavioural experiments, Alzheimer dementia, Neurochemistry, Translational neurosciences, Brain ageing, Neurodegenerative brain diseases

Our current research activities are related to the field of neurochemical research in neurodegenerative disorders. As coordinator of the RP-(U)HPLC unit of the Neurochemistry & Behavior lab, we perform neurotransmitter analyses in biofluids and brain material of patients with all types of dementia. Moreover, we have expertise in conducting behavioral research, and correlating these findings with neurotransmitter data. Our current projects are related to Alzheimer's disease in Down syndrome, Parkinson-plus syndromes, and frontotemporal dementia/amyotrophic lateral sclerosis. Our main goals are to (i) identify potential neurochemical biomarkers to facilitate differential diagnosis among these disorders, and (ii) to elucidate the neurochemical pathophysiology of neuropsychiatric symptoms in dementia. Our unit works closely with the neuropathology department of the Institute Born-Bunge, at which a large brain and biofluid biobank is situated. The UHPLC unit also functions as a service facility to analyze neurotransmitter levels in biofluids/brain material of various species. Our current setup is modifiable, to analyze various compounds.

Technique

Neurochemical analytical research; ultra-high performance liquid chromatography with electrochemical detection (UHPLC-ECD); sample preparation skills; neuropathology; behavioral analytical research; behavioral assessment scales; biobanking; enzyme-linked immunosorbent assay

Users

All neuroscientists who wish to detect neurotransmitter levels in urine, cerebrospinal fluid, brain tissue or serum/plasma, among others: dopamine, serotonin, noradrenaline, adrenaline, tryptophane, MHPG, DOPAC, 5-HIAA, HVA.

Keywords

Dopaminergic, Noradrenergic, Neuropathology, Neurodegenerative disorders, Behavioural neuroscience, Serotonergic system, Hplc analysis, Biomarkers