Biology subjects

Nikoletopoulou, V.

Publications and source records attributed to Nikoletopoulou, V..

5 recordsLinked to original sources

bioRxiv2026

Independently tunable subcortical oscillators enable prefrontal control of cortical coupling

Oscillatory coherence between brain regions varies flexibly with behavioral demands, yet the circuit mechanism underlying this control remains unclear. Theta rhythm, which coordinates prefrontal-hippocampal activity, is classically attributed to a pacemaker in the medial septum (MS), with the supramammillary nucleus (SuM) as its modulator. Here we show that SuM instead operates as an independently tunable theta oscillator. In rats performing a spatial alternation task, SuM theta frequency decreased before the choice point while MS theta frequency remained stable, reducing the SuM-MS frequency mismatch in both population spiking and local field potentials. The size of this mismatch predicted theta-rhythm coordination between the medial prefrontal cortex (mPFC) and hippocampal CA1 in both the alternation task and open-field foraging. Inhibiting direct mPFC input to SuM abolished the behavior-dependent modulation of SuM frequency and disrupted mPFC-CA1 coupling. These findings place a subcortical theta oscillator under top-down prefrontal control and identify the SuM-MS frequency mismatch as a control variable for interregional coordination.

neuroscience↗

bioRxiv2022

Autophagy in parvalbumin interneurons is required for inhibitory transmission and memory via regulation of synaptic proteostasis

With the emerging role of the autophagic machinery in healthy brain development and aging, there is a pressing need to better characterize its functions in different neuronal populations, providing cellular insight into autophagy-related brain diseases. Here, we generated and characterized mice with conditional ablation of atg5 in GABAergic neurons expressing parvalbumin (PV-atg5KO), mostly comprising fast-spiking interneurons, as well as Purkinje cells in the cerebellum. Using light-sheet microscopy to image PV neurons throughout the brain, we reveal that autophagy is required for the sustenance of Purkinje cells but not of PV-interneurons. Yet, proteomic analysis showed that autophagy deficiency in cortical and hippocampal PV-interneurons alters the proteostasis of key synaptic proteins, as well as the surface expression of glutamate receptor subunits. Consistently, hippocampal autophagy-deficient PV-interneurons exhibit reduced inhibitory neurotransmission and PV-atg5KO mice display excitation-inhibition imbalance in the hippocampus and memory deficits. Our findings demonstrate a neuronal type-specific vulnerability to autophagy deficiency, while also identifying PV-interneurons as cellular substrates where autophagy is required for memory.

neuroscience↗

bioRxiv2022

Autophagy degrades myelin proteins and is essential for maintaining CNS myelin homeostasis

(Macro)autophagy comprises a major lysosome-dependent degradation mechanism which engulfs, removes and recycles unwanted cytoplasmic material, including damaged organelles and toxic protein aggregates. Although a few studies implicate autophagy in CNS demyelinating pathologies, its role, particularly in mature oligodendrocytes and CNS myelin, remains poorly studied. Here, using both pharmacological and genetic inhibition of the autophagic machinery, we provide evidence that autophagy is an essential mechanism for oligodendrocyte maturation in vitro. Our study reveals that two core myelin proteins, namely proteolipid protein (PLP) and myelin basic protein (MBP) are incorporated into autophagosomes in oligodendrocytes, resulting in their degradation. Furthermore, we ablated atg5, a core gene of the autophagic machinery, specifically in myelinating glial cells in vivo by tamoxifen administration (plp-CreERT2; atg5F/F) and showed that myelin maintenance is perturbed, leading to PLP accumulation. Significant morphological defects in myelin membrane such as decompaction accompanied with increased axonal degeneration are observed. As a result, the mice exhibit behavioral deficits. In summary, our data highlight that the maintenance of adult myelin homeostasis in the CNS requires the involvement of a fully functional autophagic machinery.

neuroscience↗

bioRxiv2022

Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling

Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, we show that the protein AuTophaGy 5 (ATG5) functions in neurons to regulate the cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA R1, which sequesters the PKA catalytic subunit and diminishes the cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins mediating AMPAR trafficking. Glutamatergic neurons-confined ATG5 deletion augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.

neuroscience↗

bioRxiv2020

Long-term synaptic depression triggers local biogenesis of autophagic vesicles in dendrites and requires autophagic degradation

In neurons, biogenesis of autophagic vesicles (AVs) is spatially confined to the axon tip under baseline conditions. However, it remains unknown whether their biogenesis can be induced in other neuronal compartments following synaptic activity in order to serve local functions. Here, we show that both major types of long-term synaptic depression (LTD), a form of plasticity expressed by the shrinkage and elimination of dendritic spines, trigger the rapid and local biogenesis of AVs in post-synaptic dendrites. In return, autophagy is indispensable for LTD, as either genetic ablation of atg5 in pyramidal neurons or acute pharmacological inhibition of AV biogenesis totally prevents LTD induction. Using quantitative proteomic profiling of purified AVs, we reveal that upon LTD the autophagic cargo is significantly enriched for synaptic proteins, as well as modulators of the actin cytoskeleton and autism-implicated proteins. In line with these findings, a mild autophagy deficit is sufficient to impair behavioral flexibility, a cognitive function that requires efficient LTD. Therefore, local synthesis and assembly of the autophagic machinery in dendrites ensure the elimination of synaptic structures via degradation of their components, facilitating plasticity and associated behaviors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=165 HEIGHT=200 SRC="FIGDIR/small/983965v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1a7bc14org.highwire.dtl.DTLVardef@12cece0org.highwire.dtl.DTLVardef@738687org.highwire.dtl.DTLVardef@8518af_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefKallergi, Daskalaki and colleagues demonstrate that autophagy is cell autonomously required in pyramidal excitatory neurons for the induction of long-term synaptic depression (LTD). They uncover the novel and local biogenesis of autophagic vesicles (AVs) in dendrites upon LTD, by which post-synaptic components are rapidly accessible on-site for autophagic degradation. Using quantitative proteomics on purified AVs, they reveal that upon LTD the autophagic cargo is enriched in synaptic, cytoskeletal and autism-implicated proteins. HighlightsO_LIAutophagy is required cell-autonomously in pyramidal neurons for LTD. C_LIO_LINMDAR- and mGluR-mediated LTD trigger the local biogenesis of autophagic vesicles in dendrites. C_LIO_LIAutophagic vesicles sequester primarily synaptic and cytoskeletal cargo upon LTD. C_LIO_LIMild impairment in autophagy leads to deficits in cognitive flexibility. C_LI

neuroscience↗