Biology subjects

Bergami, M.

Publications and source records attributed to Bergami, M..

6 recordsLinked to original sources

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↗

bioRxiv2025

Brain injury reactivates a developmental program driving genesis and integration of transient LGE-class interneurons

Brain lesions can unlock a latent neurogenic potential in parenchymal astrocytes. However, the identity of their neuronal progeny has remained unclear. Here, we show that neurons generated by striatal astrocytes following excitotoxic lesions are transient, yet they reach advanced stages of morphological and functional maturation and integrate into cortico-striatal-thalamic circuits. Single-cell RNA-seq mapping onto an embryonic reference revealed that these cells are not related to adult striatal neuron types but instead belong to the LGE-MEIS2/PAX6 interneuron class. Notch abrogation, which mimics neurogenic activation, drives both cortical and striatal astrocytes toward this same interneuron class, revealing a shared intrinsic commitment. In primates, LGE-MEIS2/PAX6 cells transiently populate the embryonic striatum and cortex, and through spatial transcriptomics, we reveal that in mice these cells are also present and widely distributed throughout the telencephalon during embryonic and postnatal development. Thus, unlike other vertebrates in which adult telencephalic astroglia preserve the potential to generate constitutive region-specific neurons, the homologous cells in mammals converge on the generation of a specific transient neuron class, possibly representing a reservoir for circuit plasticity in adult life.

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↗