Biology subjects

Karagogeos, D.

Publications and source records attributed to Karagogeos, D..

4 recordsLinked to original sources

bioRxiv2023

A class-specific effect of dysmyelination on the excitability of hippocampal interneurons

The role of myelination for axonal conduction is well-established in projection neurons but little is known about its significance in GABAergic interneurons. Myelination is discontinuous along interneuron axons and the mechanisms controlling myelin patterning and segregation of ion channels at the nodes of Ranvier have not been elucidated. Protein 4.1B is implicated in the organization of the nodes of Ranvier as a linker between paranodal and juxtaparanodal membrane proteins to the spectrin cytoskeleton. In the present study, 4.1B KO mice are used as a genetic model to analyze the functional role of myelin in Lhx6-positive parvalbumin and somatostatin neurons, two major classes of GABAergic neurons in the hippocampus. We show that deletion of 4.1B induces disruption of juxtaparanodal K+ channel clustering and mislocalization of nodal or heminodal Na+ channels. Strikingly, 4.1B-deficiency causes loss of myelin in GABAergic axons in the hippocampus. In particular, stratum oriens O-LM cells display severe axonal dysmyelination and a reduced excitability. This reduced excitability is associated with a decrease in occurrence probability of small amplitude synaptic inhibitory events on pyramidal cells. In contrast, stratum pyramidale fast-spiking basket cells do not appear affected. The aberrant myelination of hippocampal interneurons is also correlated with impairment of spatial memory in 4.1B KO mice. In conclusion, our results indicate a class-specific effect of dysmyelination on the excitability of hippocampal interneurons associated with a functional alteration of inhibitory drive and impairment of spatial memory.

neuroscience↗

bioRxiv2022

Rac1, Rac3 GTPases and TPC2 are required for axonal outgrowth and migration of cortical interneurons.

Rho GTPases, among them Rac1 and Rac3, are major transducers of extracellular signals and are involved in multiple cellular processes. In cortical interneurons, the neurons that control excitation/inhibition balance of cortical circuits, Rac1 and Rac3 are essential for their development. Ablation of both, leads to a severe reduction in the numbers of mature interneurons found in the murine cortex, which is partially due to abnormal cell cycle progression of interneuron precursors and defective formation of their growth cones. Here we present new evidence that upon Rac1 and Rac3 ablation, centrosome, Golgi complex and lysosome positioning are significantly perturbed, thus affecting both interneuron migration and axon growth. Moreover, for the first time we provide evidence of altered expression and localization of the two-pore channel 2 (TPC2) voltage-gated ion channel that mediates Ca2+ release. Pharmacological inhibition of TPC2 negatively affected axonal growth and migration of interneurons. Our data taken together suggest that TPC2 contributes to the severe phenotype in axon growth initiation, extension and interneuron migration in the absence of Rac1 and Rac3. SUMMARY STATEMENTRac1/3 severely affect cortical interneuron migration by affecting centrosome, Golgi and lysosome positioning. TPC2 likely contributes to the phenotype by decreasing axonogenesis and somatic migration.

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↗

bioRxiv2020

Early postnatal inhibitory circuit development in the mouse medial prefrontal and primary somatosensory cortex

The prefrontal cortex (PFC) is characterized by protracted maturation. The cellular mechanisms controlling the early development of prefrontal circuits are still largely unknown. Our study delineates the developmental cellular processes in the mouse medial PFC (mPFC) during the second and third postnatal weeks and characterizes their contribution to the changes in network activity. We show that spontaneous inhibitory postsynaptic currents (sIPSC) are increased while spontaneous excitatory postsynaptic currents (sEPSC) are reduced from the second to the third postnatal week. Drug application suggested that the increased sEPSC frequency in mPFC at P10 is due to depolarizing GABAA receptor (GABAAR) function. To further validate this, perforated patch-clamp recordings were obtained and the expression levels of K-Cl co-transporter 2 (KCC2) protein were examined. The reversal potential of IPSCs in response to current stimulation was significantly more depolarized at P10 compared to P20 while KCC2 expression is decreased. Moreover, the number of parvalbumin-expressing GABAergic interneurons increase from P10 to P20 in the mPFC and their intrinsic electrophysiological properties significantly mature. Using computational modeling, we show that the developmental changes in synaptic and intrinsic properties of mPFC neurons contribute to the enhanced network activity in the juvenile compared to neonatal mPFC.

neuroscience↗