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Kula, B.

Publications and source records attributed to Kula, B..

4 recordsLinked to original sources

Short-term synaptic plasticity at neuron-OPC synapses in the corpus callosum during postnatal development of mice: experimental and computational study

Neuronal circuits rely on precisely timed synaptic transmission and plasticity, which are established through activity-dependent maturation during development. While these processes are well characterized at neuronal synapses, far less is known about how synaptic communication between neurons and glial cells develops. Pyramidal cortical neurons project axons through white matter where they release glutamate ectopically along their shafts and form glutamatergic synapses with oligodendrocyte precursor cells (OPCs). The functional maturation of these neuron-glia connections remains unknown. Here, using single-cell electrophysiology combined with computational modelling, we show that neuron-OPC synapses in the mouse corpus callosum undergo a pronounced developmental transformation in short-term synaptic plasticity. During the first two postnatal months, these synapses switch from strong synaptic depression to facilitation. This transition is accompanied by a shortening of synaptic delay and a reduction in asynchronous glutamate release, indicating an increase in temporal precision of neurotransmitter signalling in white matter. Computational modelling suggests that both pre- and postsynaptic changes may underlie this functional maturation. Taken together, our findings demonstrate that neuron-OPC synapses in white matter are not static but undergo developmental transition towards facilitation and temporally precise transmission that parallels the maturation trajectory of classical neuronal synapses in cortical grey matter. These results identify neuron-glia synapses in white matter as dynamic elements of developing neural circuits, and suggest that synaptic release machineries at axonal shafts in white matter and synaptic boutons in grey matter mature in a similar fashion.

neuroscience↗

The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease

Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimers disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD. Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.

neuroscience↗

Geometric principles determining the morphology of oligodendrocyte precursor cells in brain white matter

We used transgenic mice expressing membrane-tagged green fluorescence protein in the oligodendrocyte precursor cells (OPCs), high-resolution imaging, and detailed quantitative morphometric analysis to investigate the geometrical principles that govern structural organization of OPCs in the mouse corpus callosum. Our major findings are: (1) During the first two months of postnatal life in mice, total length of all OPCs processes increases via elaboration of new branches from the existing processes rather than via the appearance of new processes; (2) New branches are preferentially added to more distal sites of OPCs processes; (3) The processes of OPCs show stronger preferential alignment with the posterior-anterior brain axis rather than with the lateral-medial or dorsal-ventral brain axes; at the same time, the processes of OPCs show stronger preferential alignment with the lateral-medial than with the dorsal-ventral brain axis. Our study is the first detailed comprehensive analysis of OPCs morphology comparable to those available for neurons. It helps understanding the geometrical principles that govern structural organization of OPCs. These principles are important when taking into account that OPCs receive synaptic input from neurons and are capable of synaptic integration. Arborization and structural organization of OPCs processes is expected to influence the travel of synaptic input from the processes (where synapses are located) to the cell soma (where synaptic inputs are integrated), in analogy to how it occurs in neurons. Hence, the integrated synaptic signal at the OPCs cell soma which is likely to influence development and behavior of OPCs will depend on the cell morphology. Main PointsO_LIOPC maturation increases process length through higher-order branching. C_LIO_LINew branches are added distally while preserving local architecture of the inner domain. C_LIO_LIThe processes change their orientation depending on the local micro-environment. C_LI

neuroscience↗

D--hydroxybutyrate stabilizes the hippocampal CA3-CA1 circuit during acute insulin resistance.

1.The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely on glucose transporter 4 (GLUT4) or insulin, has shown promising clinical applicability in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of exogenous KB D--hydroxybutyrate (D-Hb) on mouse brain metabolism during acute insulin resistance (AIR). We found that both AIR and D-Hb had distinct impacts across neuronal compartments: AIR decreased synaptic activity and long-term potentiation (LTP) and impaired axonal conduction, synchronization, and action potential (AP) properties, while D-Hb rescued neuronal functions associated with axonal conduction, synchronization, and LTP. 2. Significance statementThis study investigates the impact of acute insulin resistance on the functionality of the hippocampal circuit and the potential protective effects of ketone body supplementation. By inhibiting GLUT4 receptors to induce acute insulin resistance, we reveal several detrimental changes caused by impaired neuronal glucose uptake. These changes include impairments in synaptic activity, axonal conduction, and neuronal firing properties. The study further examines the distinctive effects of acute insulin resistance and the rescue agent D-{beta}Hb on synaptic activity, long-term potentiation, axonal conduction, synchronization, and neuronal firing. By shedding light on neuronal responses during insulin resistance, this investigation advances our understanding of neurological disorders associated with hypometabolism and highlights the potential therapeutic value of D-{beta}Hb.

neuroscience↗