scholarly journals KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels

2018 ◽  
Author(s):  
Marie Goutierre ◽  
Sana Al Awabdh ◽  
Emeline François ◽  
Daniel Gomez-Dominguez ◽  
Theano Irinopoulou ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Membrane Trafficking ◽  
Neuronal Excitability ◽  
Reversal Potential ◽  
Autism Spectrum ◽  
Network Activity ◽  
Resting Membrane Potential ◽  
Hippocampal Activity ◽  
Gaba Signaling ◽  
Excitatory Gaba

AbstractThe K+/Cl− co-transporter KCC2 (SLC12A5) regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in several neurological and psychiatric disorders including epilepsy, neuropathic pain and autism spectrum disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents was depolarized in KCC2 knockdown neurons, this shift was fully compensated by depolarization of their resting membrane potential. This effect was due to downregulation of Task-3 leak potassium channels that we show require KCC2 for membrane trafficking. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis that could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that concur to perturb network activity, thus offering novel targets for therapeutic intervention.

scholarly journals Excitatory GABA in Rodent Developing Neocortex In Vitro

2008 ◽  
Vol 100 (2) ◽  
pp. 609-619 ◽  
Author(s):  
Sylvain Rheims ◽  
Marat Minlebaev ◽  
Anton Ivanov ◽  
Alfonso Represa ◽  
Rustem Khazipov ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Oscillatory Activity ◽  
Resting Membrane Potential ◽  
Network Oscillations ◽  
Excitatory Gaba

GABA depolarizes immature cortical neurons. However, whether GABA excites immature neocortical neurons and drives network oscillations as in other brain structures remains controversial. Excitatory actions of GABA depend on three fundamental parameters: the resting membrane potential ( Em), reversal potential of GABA ( EGABA), and threshold of action potential generation ( Vthr). We have shown recently that conventional invasive recording techniques provide an erroneous estimation of these parameters in immature neurons. In this study, we used noninvasive single N-methyl-d-aspartate and GABA channel recordings in rodent brain slices to measure both Em and EGABA in the same neuron. We show that GABA strongly depolarizes pyramidal neurons and interneurons in both deep and superficial layers of the immature neocortex (P2–P10). However, GABA generates action potentials in layer 5/6 (L5/6) but not L2/3 pyramidal cells, since L5/6 pyramidal cells have more depolarized resting potentials and more hyperpolarized Vthr. The excitatory GABA transiently drives oscillations generated by L5/6 pyramidal cells and interneurons during development (P5–P12). The NKCC1 co-transporter antagonist bumetanide strongly reduces [Cl−]i, GABA-induced depolarization, and network oscillations, confirming the importance of GABA signaling. Thus a strong GABA excitatory drive coupled with high intrinsic excitability of L5/6 pyramidal neurons and interneurons provide a powerful mechanism of synapse-driven oscillatory activity in the rodent neocortex in vitro. In the companion paper, we show that the excitatory GABA drives layer-specific seizures in the immature neocortex.

Spontaneous Development of Synchronous Oscillatory Activity During Maturation of Cortical Networks In Vitro

2002 ◽  
Vol 88 (5) ◽  
pp. 2196-2206 ◽  
Author(s):  
Thoralf Opitz ◽  
Ana D. De Lima ◽  
Thomas Voigt
Keyword(s):  
Large Scale ◽  
Reversal Potential ◽  
Neuronal Population ◽  
Network Activity ◽  
Oscillatory Activity ◽  
Pharmacological Intervention ◽  
Resting Membrane Potential ◽  
Cortical Networks ◽  
Synchronous Network

Recent studies have focused attention on mechanisms of spontaneous large-scale wavelike activity during early development of the neocortex. In this study, we describe and characterize synchronous neuronal activity that occurs in cultured cortical networks naturally without pharmacological intervention. The synchronous activity that can be detected by means of Fluo-3 fluorescence imaging starts to develop at the beginning of the second week in culture and eventually includes the entire neuronal population about 1 wk later. A synchronous increase of [Ca2+]i in the neuronal population is associated with a burst of action potentials riding on a long-lasting depolarization recorded in a single cell. It is suggested that this depolarization results directly from synaptic current, which was comprised of at least three different components mediated by AMPA, N-methyl-d-aspartate (NMDA), and GABAA receptors. We never observed a gradually depolarizing pacemaker potential and found no evidence for a change of excitability during inter-burst periods. However, we found evidence for a period of synaptic depression after bursts. Network excitability recovers gradually over seconds from this depression that can explain the episodic nature of spontaneous network activity. Using pharmacological manipulation to investigate the propagation of activity in the network, we show that synchronous network activity depends on both glutamatergic and GABAAergic neurotransmission during a brief period. Reversal potential of GABAA receptor-mediated current was found to be significantly more positive than resting membrane potential both at 1 and 2 wk in culture, suggesting depolarizing action of GABA. However, in cultures older than 2 wk, inhibition of GABAAreceptors does not result in block of synchronous network activity but in modulation of burst width and frequency.

GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations

2007 ◽  
Vol 87 (4) ◽  
pp. 1215-1284 ◽  
Author(s):  
Yehezkel Ben-Ari ◽  
Jean-Luc Gaiarsa ◽  
Roman Tyzio ◽  
Rustem Khazipov
Keyword(s):  
Synapse Formation ◽  
Early Stage ◽  
Chloride Concentration ◽  
Brain Structures ◽  
Network Activity ◽  
Strong Impact ◽  
Gaba Signaling ◽  
Immature Neurons ◽  
Excitatory Gaba ◽  
And Migration

Developing networks follow common rules to shift from silent cells to coactive networks that operate via thousands of synapses. This review deals with some of these rules and in particular those concerning the crucial role of the neurotransmitter γ-aminobuytric acid (GABA), which operates primarily via chloride-permeable GABAAreceptor channels. In all developing animal species and brain structures investigated, neurons have a higher intracellular chloride concentration at an early stage leading to an efflux of chloride and excitatory actions of GABA in immature neurons. This triggers sodium spikes, activates voltage-gated calcium channels, and acts in synergy with NMDA channels by removing the voltage-dependent magnesium block. GABA signaling is also established before glutamatergic transmission, suggesting that GABA is the principal excitatory transmitter during early development. In fact, even before synapse formation, GABA signaling can modulate the cell cycle and migration. The consequence of these rules is that developing networks generate primitive patterns of network activity, notably the giant depolarizing potentials (GDPs), largely through the excitatory actions of GABA and its synergistic interactions with glutamate signaling. These early types of network activity are likely required for neurons to fire together and thus to “wire together” so that functional units within cortical networks are formed. In addition, depolarizing GABA has a strong impact on synaptic plasticity and pathological insults, notably seizures of the immature brain. In conclusion, it is suggested that an evolutionary preserved role for excitatory GABA in immature cells provides an important mechanism in the formation of synapses and activity in neuronal networks.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

Endocannabinoid system in the neurodevelopment of GABAergic interneurons: implications for neurological and psychiatric disorders

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Chang-geng Song ◽  
Xin Kang ◽  
Fang Yang ◽  
Wan-qing Du ◽  
Jia-jia Zhang ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Network Activity ◽  
Inhibitory Neurons ◽  
Gabaergic Interneurons ◽  
Neural Stem Progenitor Cells ◽  
The Central Nervous System ◽  
Interneuron Development

Abstract In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.

scholarly journals Substance P Enhances NMDA Channel Function in Hippocampal Dentate Gyrus Granule Cells

1998 ◽  
Vol 80 (1) ◽  
pp. 113-119 ◽  
Author(s):  
David N. Lieberman ◽  
Istvan Mody
Keyword(s):  
Substance P ◽  
Dentate Gyrus ◽  
Granule Cells ◽  
Excitatory Amino Acid ◽  
Calcium Influx ◽  
Network Activity ◽  
Hippocampal Dentate Gyrus ◽  
Adult Rat ◽  
Channel Function ◽  
Nmda Channel

Lieberman, David N. and Istvan Mody. Substance P enhances NMDA channel function in hippocampal dentate gyrus granule cells. J. Neurophysiol. 80: 113–119, 1998. Substance P (SP)–containing afferents and the NK-1 tachykinin receptor to which SP binds are present in the dentate gyrus of the rat; however, direct actions of SP on principal cells have not been demonstrated in this brain region. We have examined the effect of SP on N-methyl-d-aspartate (NMDA) channels from acutely isolated dentate gyrus granule cells of adult rat hippocampus to assess the ability of SP to regulate glutamatergic input. SP produces a robust enhancement of single NMDA channel function that is mimicked by the NK-1–selective agonist Sar9, Met(O2)11-SP. The SP-induced prolongation of NMDA channel openings is prevented by the selective NK-1 receptor antagonist (+)-(2 S,3 S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994). Calcium influx or activation of protein kinase C were not required for the SP-induced increase in NMDA channel open durations. The dramatic enhancement of excitatory amino acid–mediated excitability by SP places this neuropeptide in a key position to gate activation of hippocampal network activity.

Characterization of synaptically mediated fast and slow inhibitory processes in piriform cortex in an in vitro slice preparation

1988 ◽  
Vol 59 (5) ◽  
pp. 1352-1376 ◽  
Author(s):  
G. F. Tseng ◽  
L. B. Haberly
Keyword(s):  
Membrane Potential ◽  
Piriform Cortex ◽  
Reversal Potential ◽  
Pyramidal Cells ◽  
Membrane Depolarization ◽  
Resting Membrane Potential ◽  
Excitatory Postsynaptic Potential ◽  
Pentobarbital Sodium ◽  
Postsynaptic Potential ◽  
Conductance Increase

1. Intracellular recordings were obtained from anatomically verified layer II pyramidal cells in slices from rat piriform cortex cut perpendicular to the surface. 2. Responses to afferent and association fiber stimulation at resting membrane potential consisted of a depolarizing potential followed by a late hyperpolarizing potential (LHP). Membrane polarization by current injection revealed two components in the depolarizing potential: an initial excitatory postsynaptic potential (EPSP) followed at brief latency by an inhibitory postsynaptic potential (IPSP) that inverted with membrane depolarization and truncated the duration of the EPSP. 3. The early IPSP displayed the following characteristics suggesting mediation by gamma-aminobutyric acid (GABA) receptors linked to Cl- channels: associated conductance increase, sensitivity to increases in internal Cl- concentration, blockage by picrotoxin and bicuculline, and potentiation by pentobarbital sodium. The reversal potential was in the depolarizing direction with respect to resting membrane potential so that the inhibitory effect was exclusively via current shunting. 4. The LHP had an associated conductance increase and a reversal potential of -90 mV in normal bathing medium that shifted according to Nernst predictions for a K+ potential with changes in external K+ over the range 4.5-8 mM indicating mediation by the opening of K+ channels and ruling out an electrogenic pump origin. 5. Lack of effect of bath-applied 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) or internally applied ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) on the LHP and failure of high amplitude, direct membrane depolarization to evoke a comparable potential, argue against endogenous mediation of the LHP by a Ca2+ activated K+ conductance [gK(Ca)]. However, an apparent endogenously mediated gK(Ca) with a duration much greater than the LHP was observed in a low percent of layer II pyramidal cells. Lack of effect of 8-Br-cAMP also indicates a lack of dependence of the LHP on cAMP. 6. Other characteristics of the LHP that were demonstrated include: a lack of blockage by GABAA receptor antagonists, a probable voltage sensitivity (decrease in amplitude in the depolarizing direction), and an apparent brief onset latency (less than 10 ms) when the early IPSP was blocked by picrotoxin. The LHP was unaffected by pentobarbital sodium when the early IPSP was blocked by picrotoxin. 7. Both the LHP and early IPSP were blocked by low Ca2+/high Mg2+, consistent with disynaptic mediation.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Liver X receptor β regulates the development of the dentate gyrus and autistic-like behavior in the mouse

2018 ◽  
Vol 115 (12) ◽  
pp. E2725-E2733 ◽  
Author(s):  
Yulong Cai ◽  
Xiaotong Tang ◽  
Xi Chen ◽  
Xin Li ◽  
Ying Wang ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Neural Progenitor Cells ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Liver X Receptor ◽  
Self Renewal ◽  
Spectrum Disorders ◽  
Deficient Mice

The dentate gyrus (DG) of the hippocampus is a laminated brain region in which neurogenesis begins during early embryonic development and continues until adulthood. Recent studies have implicated that defects in the neurogenesis of the DG seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Liver X receptor β (LXRβ) has recently emerged as an important transcription factor involved in the development of laminated CNS structures, but little is known about its role in the development of the DG. Here, we show that deletion of the LXRβ in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and granule cell differentiation. We also found that expression of Notch1, a central mediator of progenitor cell self-renewal, is reduced in LXRβ-null mice. In addition, LXRβ deletion in mice results in autistic-like behaviors, including abnormal social interaction and repetitive behavior. These data reveal a central role for LXRβ in orchestrating the timely differentiation of neural progenitor cells within the DG, thereby providing a likely explanation for its association with the genesis of autism-related behaviors in LXRβ-deficient mice.

Going Their Separate Ways: Dissociation of Hippocampal and Dorsolateral Prefrontal Activation during Episodic Retrieval and Post-retrieval Processing

2010 ◽  
Vol 22 (3) ◽  
pp. 513-525 ◽  
Author(s):  
Sarah L. Israel ◽  
Tyler M. Seibert ◽  
Michelle L. Black ◽  
James B. Brewer
Keyword(s):  
Episodic Memory ◽  
Memory Retrieval ◽  
Relative Increase ◽  
Network Activity ◽  
Default Network ◽  
Episodic Retrieval ◽  
Retrieval Task ◽  
Paired Associates ◽  
Hippocampal Activity ◽  
Dorsolateral Prefrontal

Hippocampal activity is modulated during episodic memory retrieval. Most consistently, a relative increase in activity during confident retrieval is observed. Dorsolateral prefrontal cortex (DLPFC) is also activated during retrieval, but may be more generally activated during cognitive-control processes. The “default network,” regions activated during rest or internally focused tasks, includes the hippocampus, but not DLPFC. Therefore, DLPFC and the hippocampus should diverge during difficult tasks suppressing the default network. It is unclear, however, whether a difficult episodic memory retrieval task would suppress the default network due to difficulty or activate it due to internally directed attention. We hypothesized that a task requiring episodic retrieval followed by rumination on the retrieved item would increase DLPFC activity, but paradoxically reduce hippocampal activity due to concomitant suppression of the default network. In the present study, blocked and event-related fMRI were used to examine hippocampal activity during episodic memory recollection and postretrieval processing of paired associates. Subjects were asked to make living/nonliving judgments about items visually presented (classify) or items retrieved from memory (recall–classify). Active and passive baselines were used to differentiate task-related activity from default-network activity. During the “recall–classify” task, anterior hippocampal activity was selectively reduced relative to “classify” and baseline tasks, and this activity was inversely correlated with DLPFC. Reaction time was positively correlated with DLPFC activation and default-network/hippocampal suppression. The findings demonstrate that frontal and hippocampal activity are dissociated during difficult episodic retrieval tasks and reveal important considerations for interpreting hippocampal activity associated with successful episodic retrieval.

Modulation of membrane potential by an acetylcholine-activated potassium current in trout atrial myocytes

2007 ◽  
Vol 292 (1) ◽  
pp. R388-R395 ◽  
Author(s):  
Cristina E. Molina ◽  
Hans Gesser ◽  
Anna Llach ◽  
Lluis Tort ◽  
Leif Hove-Madsen
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Ventricular Myocytes ◽  
Reversal Potential ◽  
Membrane Potentials ◽  
Resting Membrane Potential ◽  
Atrial Myocytes ◽  
Atrial Tissue ◽  
Isolated Cardiac Myocytes ◽  
Inwardly Rectifying

Application of the current-clamp technique in rainbow trout atrial myocytes has yielded resting membrane potentials that are incompatible with normal atrial function. To investigate this paradox, we recorded the whole membrane current ( Im) and compared membrane potentials recorded in isolated cardiac myocytes and multicellular preparations. Atrial tissue and ventricular myocytes had stable resting potentials of −87 ± 2 mV and −83.9 ± 0.4 mV, respectively. In contrast, 50 out of 59 atrial myocytes had unstable depolarized membrane potentials that were sensitive to the holding current. We hypothesized that this is at least partly due to a small slope conductance of Im around the resting membrane potential in atrial myocytes. In accordance with this hypothesis, the slope conductance of Im was about sevenfold smaller in atrial than in ventricular myocytes. Interestingly, ACh increased Im at −120 mV from 4.3 pA/pF to 27 pA/pF with an EC50 of 45 nM in atrial myocytes. Moreover, 3 nM ACh increased the slope conductance of Im fourfold, shifted its reversal potential from −78 ± 3 to −84 ± 3 mV, and stabilized the resting membrane potential at −92 ± 4 mV. ACh also shortened the action potential in both atrial myocytes and tissue, and this effect was antagonized by atropine. When applied alone, atropine prolonged the action potential in atrial tissue but had no effect on membrane potential, action potential, or Im in isolated atrial myocytes. This suggests that ACh-mediated activation of an inwardly rectifying K+ current can modulate the membrane potential in the trout atrial myocytes and stabilize the resting membrane potential.

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