Biology subjects

Jevtic, M.

Publications and source records attributed to Jevtic, M..

6 recordsLinked to original sources

bioRxiv2026

Physiological learning involves intrasynaptic reorganization of GluA1-containing AMPA receptors

Learning and memory formation depend on persistent modifications of excitatory synaptic transmission in the hippocampus through changes in AMPA receptor (AMPAR) content and properties at potentiated synapses. However, directly demonstrating such changes after physiological, behavior-driven learning in the intact brain has remained technically difficult. Using SDS-digested freeze-fracture replica labeling (SDS-FRL), we examined the density and nanoscale localization of AMPAR subunits GluA1, GluA2, and GluA3 in the mouse hippocampal CA1 pyramidal cells. GluA2 density was higher than GluA1 and GluA3 densities at both synaptic and extrasynaptic sites, consistent with previous studies showing that AMPARs in CA1 pyramidal cells mostly contain GluA2. The extrasynaptic density of GluA3 was substantially lower than those of GluA1 and GluA2, pointing to distinct trafficking mechanisms. GluA1- and GluA2-containing receptors were enriched at synaptic peripheries, whereas GluA3 was more centrally localized and clustered, a subunit-specific intrasynaptic organization consistent with differential roles in plasticity. To investigate learning-induced reorganization, we combined the inhibitory avoidance, hippocampus-dependent contextual learning paradigm with SDS-FRL in the CA1 stratum radiatum. Learning induced a selective increase in synaptic GluA1 density accompanied by a concurrent decrease in GluA2 density, consistent with a compositional shift toward higher-conductance GluA1-containing receptors, specifically in the proximal CA1 area. Strikingly, we found a redistribution of GluA1 from the synaptic periphery toward the center, accompanied by increased clustering. These findings reveal intrasynaptic receptor redistribution alongside subunit composition change, a nanoscale molecular signature at CA3-CA1 synapses, which may constitute a mechanism of hippocampal memory formation in physiological learning.

neuroscience↗

bioRxiv2026

Mitochondrial turnover at central GABAergic synapses governs vulnerability to epileptic seizures

Mitochondrial dysfunction has long been known to underlie neurodegeneration, yet the contribution of mitochondrial turnover dynamics to functional aspects of defined synaptic circuits remains poorly understood. Here, we show that the mitochondrial proteome and turnover rates of hippocampal glutamatergic and GABAergic neurons is differentially remodelled by experience, with distal axon terminals of somatostatin-positive neurons exhibiting most dramatic changes, suggesting a form of metabolic plasticity at GABAergic synapses coupled to circuit activity. Conditional ablation of the mitochondrial transport proteins MIRO1 or TRAK1 (whose human mutations cause congenital epilepsy) stalled turnover at axon terminals driving loss of cristae, without affecting synapse or neuron integrity. The resulting reduction in synaptic GABA levels destabilized network oscillations and led to hyperexcitability, culminating in recurrent seizures and premature death. Post-weaning gene therapy efficiently reversed mitochondrial alterations and ameliorated the epileptic phenotype, underscoring the crucial role of mitochondrial turnover at central GABAergic synapses for balancing network excitability.

neuroscience↗

bioRxiv2023

Enhanced mitochondrial fusion during a critical period of synaptic plasticity in adult-born neurons

Integration of new neurons into adult hippocampal circuits is a process coordinated by local and long-range synaptic inputs. To achieve stable integration and uniquely contribute to hippocampal function, immature neurons are endowed with a critical period of heightened synaptic plasticity, yet it remains unclear which mechanisms sustain this form of plasticity during neuronal maturation. We found that, as new neurons enter their critical period, a transient surge in fusion dynamics stabilizes elongated mitochondrial morphologies in dendrites to fuel synaptic plasticity. Conditional ablation of fusion dynamics to prevent mitochondrial elongation selectively impaired spine plasticity and synaptic potentiation, disrupting neuronal competition for stable circuit integration, ultimately leading to decreased survival. Despite profuse mitochondrial fragmentation, manipulation of competition dynamics was sufficient to restore neuronal survival, but left neurons poorly responsive to experiences at the circuit level. Thus, by enabling synaptic plasticity during the critical period, mitochondrial fusion facilitates circuit remodeling by adult-born neurons.

neuroscience↗

bioRxiv2023

Functional synapses between small cell lung cancer and glutamatergic neurons

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, clinical recurrence and high rate of mortality. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified a strong and consistent signal for neuronal, synaptic, and glutamatergic signaling gene sets in murine and human SCLC. We show that SCLC cells have the ability to develop intimate contacts with neuronal glutamatergic terminals in vitro, in autochthonous primary lung tumors and in brain-engrafted tumors. These contacts can develop into bona fide synapses, allowing SCLC cells to receive glutamatergic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we show that SCLC cells derive a robust proliferation advantage when co-cultured with neurons. Moreover, the repression of glutamate release and the stimulation of the inhibitory glutamate receptor GRM8 displayed therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells appear to hijack glutamatergic signaling to sustain tumor growth, thereby exposing a novel entry route for therapeutic intervention.

cancer biology↗

bioRxiv2021

Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L

The transition between quiescence and activation in neural stem and progenitor cells (NSPCs) is coupled to reversible changes in energy metabolism with key implications for life-long NSPC self-renewal and neurogenesis. How this metabolic plasticity is ensured between NSPC activity states is unclear. We found that a state-dependent rewiring of the mitochondrial proteome by the peptidase YME1L is required to preserve NSPC self-renewal in the adult brain. YME1L-mediated proteome rewiring regulates the rate of fatty acid oxidation (FAO) for replenishing Krebs cycle intermediates and dNTP precursors, which are required to sustain NSPC amplification. Yme1l deletion irreversibly shifts the metabolic profile of NSPCs away from a FAO-dependent state resulting in defective self-renewal, premature differentiation and NSPC pool depletion. Our results disclose an important role for YME1L in coordinating the switch between metabolic states of NSPCs and suggest that NSPC fate is regulated by compartmentalized changes in protein network dynamics.

neuroscience↗

bioRxiv2019

Mitochondrial fusion in reactive astrocytes coordinates local metabolic domains to promote vascular repair

Astrocytes have emerged for playing important roles in brain tissue repair, however the underlying mechanisms remain poorly understood. We show that acute injury and blood-brain barrier disruption trigger the formation of a prominent mitochondrial-enriched compartment in astrocytic end-feet which enables vascular remodeling. Integrated imaging approaches revealed that this mitochondrial clustering is part of an adaptive response regulated by fusion dynamics. Astrocyte-specific conditional deletion of Mitofusin 2 (Mfn2) suppressed perivascular mitochondrial clustering and disrupted mitochondria-ER contact sites. Functionally, two-photon imaging experiments showed that these structural changes were mirrored by impaired mitochondrial Ca2+ uptake leading to abnormal cytosolic transients within end-feet in vivo. At the tissue level, a compromised vascular complexity in the lesioned area was restored by boosting mitochondrial-ER perivascular tethering in MFN2-deficient astrocytes. These data unmask a crucial role for mitochondrial dynamics in coordinating astrocytic local domains and have important implications for repairing the injured brain.

cell biology↗