1,720,974 research outputs found
A Reappraisal of GAT-1 Localization in Neocortex
Full text linkγ-Aminobutyric acid (GABA) transporter (GAT)-1, the major GABA transporter in the brain, plays a key role in modulating GABA signaling and is involved in the pathophysiology of several neuropsychiatric diseases, including epilepsy. The original description of GAT-1 as a neuronal transporter has guided the interpretation of the findings of all physiological, pharmacological, genetic, or clinical studies. However, evidence published in the past few years, some of which is briefly reviewed herein, does not seem to be consistent with a neurocentric view of GAT-1 function and calls for more detailed analysis of its localization. We therefore performed a thorough systematic assessment of GAT-1 localization in neocortex and subcortical white matter. In line with earlier work, we found that GAT-1 was robustly expressed in axon terminals forming symmetric synapses and in astrocytic processes, whereas its astrocytic expression was more diffuse than expected and, even more surprisingly, immature and mature oligodendrocytes and microglial cells also expressed the transporter. These data indicate that the era of “neuronal” and “glial” GABA transporters has finally come to a close and provide a wider perspective from which to view GABA-mediated physiological phenomena. In addition, given the well-known involvement of astrocytes, oligodendrocytes, and microglial cells in physiological as well as pathological conditions, the demonstration of functional GAT-1 in these cells is expected to provide greater insight into the phenomena occurring in the diseased brain as well as to prompt a reassessment of earlier findings
Clozapine up-regulates the expression of the vesicular GABA transporter (VGAT) in rat cerebral cortex
No full textNeuronal localization of the GABA transporter GAT-3 in human cerebral cortex: A procedural artifact?
No full textFew, Activity-Dependent, and Ubiquitous VGLUT1/VGAT Terminals in Rat and Mouse Brain
Full text linkIn the neocortex of adult rats VGLUT1 and VGAT co-localize in axon terminals which form both symmetric and asymmetric synapses. They are expressed in the same synaptic vesicles which participate in the exo-endocytotic cycle. Virtually nothing, however, is known on whether VGLUT1/VGAT co-localization occurs in other brain regions. We therefore mapped the distribution of terminals co-expressing VGLUT1/VGAT in the striatum, hippocampus, thalamus, and cerebellar and cerebral cortices of rats and mice. Confocal microscopy analysis revealed that, in both rat and mouse brain, VGLUT1/VGAT+ terminals were present in all brain regions studied, and that their percentage was low and comparable in both species. These results provide the first demonstration that co-expression of VGLUT1 and VGAT is a widespread phenomenon. Since VGLUT1/VGAT+ axon terminals are regulated in an activity-dependent manner and co-release glutamate and GABA, we hypothesize that, though not numerous, they can contribute to regulating excitation/inhibition balance in physiological conditions, thereby playing a role in several neurological and psychiatric diseases
Levetiracetam Affects Differentially Presynaptic Proteins in Rat Cerebral Cortex
Full text linkPresynaptic proteins are potential therapeutic targets for epilepsy and other neurological diseases. We tested the hypothesis that chronic treatment with the SV2A ligand levetiracetam affects the expression of other presynaptic proteins. Results showed that in rat neocortex no significant difference was detected in SV2A protein levels in levetiracetam treated animals compared to controls, whereas levetiracetam post-transcriptionally decreased several vesicular proteins and increased LRRK2, without any change in mRNA levels. Analysis of SV2A interactome indicates that the presynaptic proteins regulation induced by levetiracetam reported here is mediated by this interactome, and suggests that LRRK2 plays a role in forging the pattern of effects
PrPC Controls via Protein Kinase A the Direction of Synaptic Plasticity in the Immature Hippocampus
No full textThe cellular form of prion protein PrPC is highly expressed in the brain, where it can be converted into its abnormally folded isoform PrPSc to cause neurodegenerative diseases. Its predominant synaptic localization suggests a crucial role in synaptic signaling. Interestingly, PrPC is developmentally regulated and its high expression in the immature brain could be instrumental in regulating neurogenesis and cell proliferation. Here, PrPC-deficient (Prnp0/0) mice were used to assess whether the prion protein is involved in synaptic plasticity processes in the neonatal hippocampus. To this aim, calcium transients associated with giant depolarizing potentials, a hallmark of developmental networks, were transiently paired with mossy fiber activation in such a way that the two events were coincident. While this procedure caused long-term potentiation (LTP) in wild-type (WT) animals, it caused long-term depression (LTD) in Prnp0/0 mice. Induction of LTP was postsynaptic and required the activation of cAMP-dependent protein kinase A (PKA) signaling. The induction of LTD was presynaptic and relied on G-protein-coupled GluK1 receptor and protein lipase C. In addition, at emerging CA3-CA1 synapses in WT mice, but not in Prnp0/0 mice, pairing Schaffer collateral stimulation with depolarization of CA1 principal cells induced LTP, known to be PKA dependent. Postsynaptic infusion of a constitutively active isoform of PKA catalytic subunit Cα into CA1 and CA3 principal cells in the hippocampus of Prnp0/0 mice caused a persistent synaptic facilitation that was occluded by subsequent pairing. These data suggest that PrPC plays a crucial role in regulating via PKA synaptic plasticity in the developing hippocampus
An open-science computational model of organelle acidification to integrate putative mechanisms of synaptic vesicle acidification and filling
Full text linkOrganelle acidification has essential implications for the development of degenerative disorders in the brain and heart, but the experimental characterization of these dynamic compartments in native-like contexts is challenging. Computational models can help organize and refine putative mechanisms of organelle acidifications in the same way they helped with brain and heart electrophysiology. Unfortunately, existing models of organelle acidification are not easy to access and operate. Here, we ported the existing model of lysosome acidification into an open-source Python implementation. Furthermore, we hosted this implementation in Google Colab, so everyone with a browser can simulate organelle acidification without a technical background. Finally, we demonstrate how this model can be extended to new organelle types by providing simulations of synaptic vesicle acidification and filling that incorporate different proposed modes of transport and can be fitted to recent experiments
Acute phencyclidine administration reduces extracellular glutamate levels and the expression of synaptophysin and SNAP-25 in rat frontal cortex
No full textVGLUT1 and VGAT are sorted to the same populations of synaptic vesicles in subsets of cortical axon terminals
No full textGlutamate and GABA mediate most of the excitatory and inhibitory synaptic transmission; they are taken up and accumulated in synaptic vesicles by specific vesicular transporters named VGLUT1-3 and VGAT, respectively. Recent studies show that VGLUT2 and VGLUT3 are co-expressed with VGAT. Because of the relevance this information has for our understanding of synaptic physiology and plasticity, we investigated whether VGLUT1 and VGAT are co-expressed in rat cortical neurons. In cortical cultures and layer V cortical terminals we observed a population of terminals expressing VGLUT1 and VGAT. Post-embedding immunogold studies showed that VGLUT1+/VGAT+ terminals formed both symmetric and asymmetric synapses. Triple-labeling studies revealed GABAergic synapses expressing VGLUT1 and glutamatergic synapses expressing VGAT. Immunoisolation studies showed that anti-VGAT immunoisolated vesicles contained VGLUT1 and anti-VGLUT1 immunoisolated vesicles contained VGAT. Finally, vesicles containing VGAT resident in glutamatergic terminals undergo active recycling. In conclusion, we demonstrate that in neocortex VGLUT1 and VGAT are co-expressed in a subset of axon terminals forming both symmetric and asymmetric synapses, that VGLUT1 and VGAT are sorted to the same vesicles and that vesicles at synapses expressing the vesicular heterotransporter participate in the exo-endocytotic cycle
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