scholarly journals Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1686
Author(s):  
Tayyaba Qureshi ◽  
Mona Bjørkmo ◽  
Kaja Nordengen ◽  
Vidar Gundersen ◽  
Tor Paaske Utheim ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Brain Slices ◽  
Gabaergic Neurons ◽  
Action Potential Firing ◽  
Wide Range ◽  
Gaba Signaling ◽  
Potential Firing ◽  
Gaba Synthesis ◽  
Neuronal Functions

GABA signaling is involved in a wide range of neuronal functions, such as synchronization of action potential firing, synaptic plasticity and neuronal development. Sustained GABA signaling requires efficient mechanisms for the replenishment of the neurotransmitter pool of GABA. The prevailing theory is that exocytotically released GABA may be transported into perisynaptic astroglia and converted to glutamine, which is then shuttled back to the neurons for resynthesis of GABA—i.e., the glutamate/GABA-glutamine (GGG) cycle. However, an unequivocal demonstration of astroglia-to-nerve terminal transport of glutamine and the contribution of astroglia-derived glutamine to neurotransmitter GABA synthesis is lacking. By genetic inactivation of the amino acid transporter Solute carrier 38 member a1 (Slc38a1)—which is enriched on parvalbumin+ GABAergic neurons—and by intraperitoneal injection of radiolabeled acetate (which is metabolized to glutamine in astroglial cells), we show that Slc38a1 mediates import of astroglia-derived glutamine into GABAergic neurons for synthesis of GABA. In brain slices, we demonstrate the role of Slc38a1 for the uptake of glutamine specifically into GABAergic nerve terminals for the synthesis of GABA depending on demand and glutamine supply. Thus, while leaving room for other pathways, our study demonstrates a key role of Slc38a1 for newly formed GABA, in harmony with the existence of a GGG cycle.

scholarly journals Endogenous γ-Aminobutyric Acid Can Excite Gonadotropin-Releasing Hormone Neurons

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5374-5379 ◽  
Author(s):  
Suzanne M. Moenter ◽  
R. Anthony DeFazio
Keyword(s):  
Firing Rate ◽  
Brain Slices ◽  
Aminobutyric Acid ◽  
Firing Activity ◽  
Action Potential Firing ◽  
Neuron Response ◽  
Gnrh Neurons ◽  
Potential Firing ◽  
Gaba Transmission

γ-Aminobutyric acid (GABA) provides a major synaptic input to GnRH neurons. GnRH neurons maintain high intracellular chloride levels and respond to exogenous GABA with depolarization and action potential firing. We examined the role of synaptic GABA type A receptor (GABAAR) activation on the firing activity of GnRH neurons. Targeted extracellular recordings were used to detect firing activity of GnRH neurons in brain slices from adult female mice. Because the brain slice preparation preserves both glutamatergic and GABAergic neuronal networks, the effects of GABAARs on GnRH neurons were isolated by blocking ionotropic glutamatergic receptors (iGluR). With iGluR blocked, many GnRH neurons remained spontaneously active. Consistent with an excitatory role for GABA, subsequent blockade of GABAARs suppressed the firing rate in active cells from diestrous females by approximately 40% (P < 0.05; n = 10). GABAAR blockade did not affect inactive cells (n = 7), indicating that GABAAR-mediated inhibition was not responsible for the lack of firing. In prenatally androgenized females, GnRH neurons exhibit larger, more frequent GABAergic postsynaptic currents than control females. Most cells from prenatally androgenized animals fired spontaneously, and the firing rate was suppressed approximately 80% after GABAAR blockade (P < 0.01; n = 8). Blocking GABAAR without blocking iGluRs increased the firing rate in GnRH neurons from diestrous females (P < 0.05; n = 6), perhaps attributable to hyperexcitability within the slice network. Our results indicate that GABAergic inputs help generate a portion of action potentials in GnRH neurons; this fraction depends on the level of GABA transmission and postsynaptic responsiveness. The complexities of the GnRH neuron response to GABA make this a potentially critical integration point for central regulation of fertility.

scholarly journals GABA receptors differentially regulate life span and health span in C. elegans through distinct downstream mechanisms

2019 ◽  
Vol 317 (5) ◽  
pp. C953-C963 ◽  
Author(s):  
Fengling Yuan ◽  
Jiejun Zhou ◽  
Lingxiu Xu ◽  
Wenxin Jia ◽  
Lei Chun ◽  
...  
Keyword(s):  
Life Span ◽  
Gaba Receptors ◽  
Health Span ◽  
Gaba A ◽  
Inhibitory Neurotransmitter ◽  
C Elegans ◽  
Physiological Processes ◽  
Gaba Signaling ◽  
Neuronal Functions

GABA, a prominent inhibitory neurotransmitter, is best known to regulate neuronal functions in the nervous system. However, much less is known about the role of GABA signaling in other physiological processes. Interestingly, recent work showed that GABA signaling can regulate life span via a metabotropic GABAB receptor in Caenorhabditis elegans. However, the role of other types of GABA receptors in life span has not been clearly defined. It is also unclear whether GABA signaling regulates health span. Here, using C. elegans as a model, we systematically interrogated the role of various GABA receptors in both life span and health span. We find that mutations in four different GABA receptors extend health span by promoting resistance to stress and pathogen infection and that two such receptor mutants also show extended life span. Different GABA receptors engage distinct transcriptional factors to regulate life span and health span, and even the same receptor regulates life span and health span via different transcription factors. Our results uncover a novel, profound role of GABA signaling in aging in C. elegans, which is mediated by different GABA receptors coupled to distinct downstream effectors.

scholarly journals Stabilizing Role of Calcium Store-Dependent Plasma Membrane Calcium Channels in Action-Potential Firing and Intracellular Calcium Oscillations

2005 ◽  
Vol 89 (6) ◽  
pp. 3741-3756 ◽  
Author(s):  
J.M.A.M. Kusters ◽  
M.M. Dernison ◽  
W.P.M. van Meerwijk ◽  
D.L. Ypey ◽  
A.P.R. Theuvenet ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Calcium Channels ◽  
Action Potential ◽  
Intracellular Calcium ◽  
Calcium Oscillations ◽  
Action Potential Firing ◽  
Calcium Store ◽  
Potential Firing

Neuromodulation by a Cytokine: Interferon-β Differentially Augments Neocortical Neuronal Activity and Excitability

2005 ◽  
Vol 93 (2) ◽  
pp. 843-852 ◽  
Author(s):  
Gergana Hadjilambreva ◽  
Eilhard Mix ◽  
Arndt Rolfs ◽  
Jana Müller ◽  
Ulf Strauss
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Membrane Resistance ◽  
Interferon Β ◽  
Action Potential Firing ◽  
Somatosensory Neurons ◽  
Potential Firing ◽  
Intracellular Process ◽  
Neuronal Functions

The immunomodulatory cytokine interferon-β (IFN-β) is used in the treatment of autoimmune diseases such as multiple sclerosis. However, the effect of IFN-β on neuronal functions is currently unknown. Intracellular recordings were conducted on somatosensory neurons of neocortical layers 2/3 and 5 exposed to IFN-β. The excitability of neurons was increased by IFN-β (10–10,000 U/ml) in two kinetically distinct, putatively independent manners. First IFN-β reversibly influenced the subthreshold membrane response by raising the membrane resistance RM 2.5-fold and the membrane time constant τ 1.7-fold dose-dependently. The effect required permanent exposure to IFN-β and was reduced in magnitude if the extracellular K+ was lowered. However, the membrane response to IFN-β in the subthreshold range was prevented by ZD7288 (a specific blocker of Ih) but not by Ni2+, carbachol, or bicuculline, pointing to a dependence on an intact Ih. Second, IFN-β enhanced the rate of action potential firing. This effect was observed to develop for >1 h when the cell was exposed to IFN-β for 5 min or >5 min and showed no reversibility (≤210 min). Current-discharge ( F-I) curves revealed a shift (prevented by bicuculline) as well as an increase in slope (prevented by carbachol and Ni2+). Layer specificity was not observed with any of the described effects. In conclusion, IFN-β influences the neuronal excitability in neocortical pyramidal neurons in vitro, especially under conditions of slightly increased extracellular K+. Our blocker experiments indicate that changes in various ionic conductances with different voltage dependencies cause different IFN-β influences on sub- and suprathreshold behavior, suggesting a more general intracellular process induced by IFN-β.

scholarly journals Avian magnetite-based magnetoreception: a physiologist's perspective

2010 ◽  
Vol 7 (suppl_2) ◽  
Author(s):  
Hervé Cadiou ◽  
Peter A. McNaughton
Keyword(s):  
Magnetic Field ◽  
Magnetic Fields ◽  
Electric Signal ◽  
Sensory Cells ◽  
Action Potential Firing ◽  
Long Distance ◽  
Electrophysiological Recordings ◽  
Wide Range ◽  
Potential Firing ◽  
Behavioural Tests

It is now well established that animals use the Earth's magnetic field to perform long-distance migration and other navigational tasks. However, the transduction mechanisms that allow the conversion of magnetic field variations into an electric signal by specialized sensory cells remain largely unknown. Among the species that have been shown to sense Earth-strength magnetic fields, birds have been a model of choice since behavioural tests show that their direction-finding abilities are strongly influenced by magnetic fields. Magnetite, a ferromagnetic mineral, has been found in a wide range of organisms, from bacteria to vertebrates. In birds, both superparamagnetic (SPM) and single-domain magnetite have been found to be associated with the trigeminal nerve. Electrophysiological recordings from cells in the trigeminal ganglion have shown an increase in action potential firing in response to magnetic field changes. More recently, histological evidence has demonstrated the presence of SPM magnetite in the subcutis of the pigeon's upper beak. The aims of the present review are to review the evidence for a magnetite-based mechanism in birds and to introduce physiological concepts in order to refine the proposed models.

scholarly journals Interconnection and synchronization of neuronal populations in the mouse medial septum/diagonal band of Broca

2015 ◽  
Vol 113 (3) ◽  
pp. 971-980 ◽  
Author(s):  
Richardson N. Leão ◽  
Zé H. Targino ◽  
Luis V. Colom ◽  
André Fisahn
Keyword(s):  
Action Potentials ◽  
Theta Rhythm ◽  
Medial Septum ◽  
Gabaergic Neurons ◽  
Action Potential Firing ◽  
Neuronal Populations ◽  
Diagonal Band ◽  
Potential Firing ◽  
Diagonal Band Of Broca ◽  
Hippocampal Theta

The medial septum/diagonal band of Broca (MS/DBB) is crucial for hippocampal theta rhythm generation (4–12 Hz). However, the mechanisms behind theta rhythmogenesis are still under debate. The MS/DBB consists, in its majority, of three neuronal populations that use acetylcholine, GABA, or glutamate as neurotransmitter. While the firing patterns of septal neurons enable the MS/DBB to generate rhythmic output critical for the generation of the hippocampal theta rhythm, the ability to synchronize these action potentials is dependent on the interconnectivity between the three major MS/DBB neuronal populations, yet little is known about intraseptal connections. Here we assessed the connectivity between pairs of MS/DBB neurons with paired patch-clamp recordings. We found that glutamatergic and GABAergic neurons provide intraseptal connections and produce sizable currents in MS/DBB postsynaptic cells. We also analyzed linear and nonlinear relationships between the action potentials fired by pairs of neurons belonging to various MS/DBB neuronal populations. Our results show that while the synchrony index for action potential firing was significantly higher in pairs of GABAergic neurons, coherence of action potential firing in the theta range was similarly low in all pairs analyzed. Recurrence analysis demonstrated that individual action potentials were more recurrent in cholinergic neurons than in other cell types. Implementing sparse connectivity in a computer model of the MS/DBB network reproduced our experimental data. We conclude that the interplay between the intrinsic membrane properties of different MS/DBB neuronal populations and the connectivity among these populations underlie the ability of the MS/DBB network to critically contribute to hippocampal theta rhythmogenesis.

scholarly journals The role of network architecture in the onset of spontaneous activity

STEMedicine ◽  
2020 ◽  
Vol 1 (1) ◽  
pp. e1 ◽  
Author(s):  
Diletta Pozzi ◽  
Nicolò Meneghetti ◽  
Anjan Roy ◽  
Beatrice Pastore ◽  
Alberto Mazzoni ◽  
...  
Keyword(s):  
Spontaneous Activity ◽  
Network Architecture ◽  
Statistical Tests ◽  
Hippocampal Slices ◽  
Brain Slices ◽  
Gabaergic Neurons ◽  
Neuronal Cultures ◽  
Optical Transients

BACKGROUND: The spontaneous activity of neuronal networks has been studied in in vitro models such as brain slices and dissociated cultures. However, a comparison between their dynamical properties in these two types of biological samples is still missing and it would clarify the role of architecture in shaping networks’ operation. METHODS: We used calcium imaging to identify clusters of neurons co-activated in hippocampal and cortical slices, as well as in dissociated neuronal cultures, from GAD67-GFP mice. We used statistical tests, power law fitting and neural modelling to characterize the spontaneous events observed. RESULTS:  In slices, we observed intermittency between silent periods, the appearance of Confined Optical Transients (COTs) and of Diffused Optical Transients (DOTs). DOTs in the cortex were preferentially triggered by the activity of neurons located in layer III-IV, poorly coincident with GABAergic neurons. DOTs had a duration of 10.2±0.3 and 8.2±0.4 seconds in cortical and hippocampal slices, respectively, and were blocked by tetrodotoxin, indicating their neuronal origin. The amplitude and duration of DOTs were controlled by NMDA and GABA-A receptors. In dissociated cultures, we observed an increased synchrony in GABAergic neurons and the presence of global synchronous events similar to DOTs, but with a duration shorter than that seen in the native tissues. CONCLUSION: We conclude that DOTs are shaped by the network architecture and by the balance between inhibition and excitation, and that they can be reproduced by network models with a minimal number of parameters.

scholarly journals Role of Cleaved PINK1 in Neuronal Development, Synaptogenesis, and Plasticity: Implications for Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Smijin K. Soman ◽  
Ruben K. Dagda
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Development ◽  
Structural Integrity ◽  
Intermembrane Space ◽  
Loss Of Function ◽  
Serine Threonine Kinase ◽  
Functional Roles ◽  
Neuronal Functions

Mitochondrial dysfunction plays a significant role in the pathogenesis of Parkinson’s disease (PD). Consistent with this concept, loss of function mutations in the serine/threonine kinase- PINK1 (PTEN-induced putative kinase-1) causes autosomal recessive early onset PD. While the functional role of f-PINK1 (full-length PINK1) in clearing dysfunctional mitochondria via mitophagy is extensively documented, our understanding of specific physiological roles that the non-mitochondrial pool of PINK1 imparts in neurons is more limited. PINK1 is proteolytically processed in the intermembrane space and matrix of the mitochondria into functional cleaved products (c-PINK1) that are exported to the cytosol. While it is clear that posttranslational processing of PINK1 depends on the mitochondria’s oxidative state and structural integrity, the functional roles of c-PINK1 in modulating neuronal functions are poorly understood. Here, we review the diverse roles played by c-PINK1 in modulating various neuronal functions. Specifically, we describe the non-canonical functional roles of PINK1, including but not limited to: governing mitochondrial movement, neuronal development, neuronal survival, and neurogenesis. We have published that c-PINK1 stimulates neuronal plasticity and differentiation via the PINK1-PKA-BDNF signaling cascade. In addition, we provide insight into how mitochondrial membrane potential-dependent processing of PINK1 confers conditional retrograde signaling functions to PINK1. Further studies delineating the role of c-PINK1 in neurons would increase our understanding regarding the role played by PINK1 in PD pathogenesis.

SK Channel Regulation of Dendritic Excitability and Dendrodendritic Inhibition in the Olfactory Bulb

2005 ◽  
Vol 94 (6) ◽  
pp. 3743-3750 ◽  
Author(s):  
Brady J. Maher ◽  
Gary L. Westbrook
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells ◽  
Brain Slices ◽  
Mitral Cell ◽  
Mitral Cells ◽  
Sk Channels ◽  
Action Potential Firing ◽  
Sk Channel ◽  
Dendritic Excitability ◽  
Potential Firing

Small-conductance calcium-activated potassium channels (SK) regulate dendritic excitability in many neurons. In the olfactory bulb, regulation of backpropagating action potentials and dendrodendritic inhibition depend on the dendritic excitability of mitral cells. We report here that SK channel currents are present in mitral cells but are not detectable in granule cells in the olfactory bulb. In brain slices from PND 14–21 mice, long step depolarizations (100 ms) in the mitral cell soma evoked a cadmium- and apamin-sensitive outward SK current lasting several hundred milliseconds. Block of the SK current unmasked an inward N-methyl-d-aspartate (NMDA) autoreceptor current due to glutamate released from mitral cell dendrites. In low extracellular Mg2+ (100 μM), brief step depolarizations (2 ms) evoked an apamin-sensitive current that was reduced by d,l-2-amino-5-phosphonopentanoic acid. In current- clamp, block of SK channels increased action potential firing in mitral cells as well as dendrodendritic inhibition. Our results indicate that SK channels can be activated either by calcium channels or NMDA channels in mitral cell dendrites, providing a mechanism for local control of dendritic excitability.

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