Research team
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.