Neuronal excitability and spontaneous synaptic transmission in the entorhinal cortex of BDNF heterozygous mice

The role of group III metabotropic glutamate receptors (mGluRs) in modulating excitatory synaptic transmission was investigated in the rat entorhinal cortex (EC) in vitro. AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) were recorded in the whole cell configuration of the patch-clamp technique from visually identified neurons in layers V and II. In layer V, bath application of the specific group III mGluR agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 500 μM) resulted in a marked facilitation of both spontaneous and activity-independent “miniature” (s/mEPSC) event frequency. The facilitatory effect of L-AP4 (100 μM) on sEPSC frequency prevailed in the presence ofdl−2-amino-5-phosphonopentanoic acid (100 μM) but was abolished by the group III antagonist (RS)-cyclopropyl-4-phosphonophenylglycine (20 μM). These data confirmed that group III mGluRs, and not N-methyl-d-aspartate (NMDA) receptors were involved in the response to L-AP4. Bath application of the specific mGluR4a agonist (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid (20 μM) also had a facilitatory effect on sEPSC frequency, suggesting involvement of mGluR4a. In layer II neurons, L-AP4 caused a reduction in sEPSC frequency but did not affect mEPSCs recorded in the presence of tetrodotoxin. These findings suggest that a group III mGluR with mGluR4a-like pharmacology is involved in modulating synaptic transmission in layer V cells of the EC. The effect on mEPSCs suggests that this receptor is located presynaptically and that its activation results in a direct facilitation of glutamate release. This novel facilitatory effect is specific to layer V and, to our knowledge, is the first report of a direct facilitatory action of group III mGluRs on synaptic transmission. In layer II, L-AP4 had an inhibitory effect on glutamate release similar to that reported in other brain regions.

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Major Role For Tonic GABAA Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Journal of Neurophysiology ◽

10.1152/jn.00223.2004 ◽

2004 ◽

Vol 92 (3) ◽

pp. 1658-1667 ◽

Cited By ~ 86

Author(s):

Mark C. Bieda ◽

M. Bruce MacIver

Keyword(s):

Synaptic Transmission ◽

Neuronal Excitability ◽

Brain Slices ◽

Pyramidal Cells ◽

Intrinsic Excitability ◽

High Potassium ◽

Ca1 Neurons ◽

Adult Rat ◽

Adult Rat Brain ◽

Sites Of Action

Anesthetics appear to produce neurodepression by altering synaptic transmission and/or intrinsic neuronal excitability. Propofol, a widely used anesthetic, has proposed effects on many targets, ranging from sodium channels to GABAA inhibition. We examined effects of propofol on the intrinsic excitability of hippocampal CA1 neurons (primarily interneurons) recorded from adult rat brain slices. Propofol strongly depressed action potential production induced by DC injection, synaptic stimulation, or high-potassium solutions. Propofol-induced depression of intrinsic excitability was completely reversed by bicuculline and picrotoxin but was strychnine-insensitive, implicating GABAA but not glycine receptors. Propofol strongly enhanced inhibitory postsynaptic currents (IPSCs) and induced a tonic GABAA-mediated current. We pharmacologically differentiated tonic and phasic (synaptic) GABAA-mediated inhibition using the GABAA receptor antagonist SR95531 (gabazine). Gabazine (20 μM) completely blocked both evoked and spontaneous IPSCs but failed to block the propofol-induced depression of intrinsic excitability, implicating tonic, but not phasic, GABAA inhibition. Glutamatergic synaptic responses were not altered by propofol (≤30 μM). Similar results were found in both interneurons and pyramidal cells and with the chemically unrelated anesthetic thiopental. These results suggest that suppression of CA1 neuron intrinsic excitability, by these anesthetics, is largely due to activation of tonic GABAA conductances; although other sites of action may play important roles in affecting synaptic transmission, which also can produce strong neurodepression. We propose that for some anesthetics, suppression of intrinsic excitability, mediated by tonic GABAA conductances, operates in conjunction with effects on synaptic transmission, mediated by other mechanisms, to depress hippocampal function during anesthesia.

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Control of motor coordination by astrocytic tonic GABA release through modulation of excitation/inhibition balance in cerebellum

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1721187115 ◽

2018 ◽

Vol 115 (19) ◽

pp. 5004-5009 ◽

Cited By ~ 22

Author(s):

Junsung Woo ◽

Joo Ok Min ◽

Dae-Si Kang ◽

Yoo Sung Kim ◽

Guk Hwa Jung ◽

...

Keyword(s):

Synaptic Transmission ◽

Motor Performance ◽

Neuronal Excitability ◽

Motor Coordination ◽

Granule Cells ◽

Cerebellar Granule Cells ◽

Gaba Release ◽

In Vivo Microdialysis ◽

Tonic Inhibition

Tonic inhibition in the brain is mediated through an activation of extrasynaptic GABAA receptors by the tonically released GABA, resulting in a persistent GABAergic inhibitory action. It is one of the key regulators for neuronal excitability, exerting a powerful action on excitation/inhibition balance. We have previously reported that astrocytic GABA, synthesized by monoamine oxidase B (MAOB), mediates tonic inhibition via GABA-permeable bestrophin 1 (Best1) channel in the cerebellum. However, the role of astrocytic GABA in regulating neuronal excitability, synaptic transmission, and cerebellar brain function has remained elusive. Here, we report that a reduction of tonic GABA release by genetic removal or pharmacological inhibition of Best1 or MAOB caused an enhanced neuronal excitability in cerebellar granule cells (GCs), synaptic transmission at the parallel fiber-Purkinje cell (PF-PC) synapses, and motor performance on the rotarod test, whereas an augmentation of tonic GABA release by astrocyte-specific overexpression of MAOB resulted in a reduced neuronal excitability, synaptic transmission, and motor performance. The bidirectional modulation of astrocytic GABA by genetic alteration of Best1 or MAOB was confirmed by immunostaining and in vivo microdialysis. These findings indicate that astrocytes are the key player in motor coordination through tonic GABA release by modulating neuronal excitability and could be a good therapeutic target for various movement and psychiatric disorders, which show a disturbed excitation/inhibition balance.

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KCC2 antagonism increases neuronal network excitability but disrupts ictogenesis in vitro

Journal of Neurophysiology ◽

10.1152/jn.00266.2019 ◽

2019 ◽

Vol 122 (3) ◽

pp. 1163-1173 ◽

Cited By ~ 2

Author(s):

Li-Yuan Chen ◽

Maxime Lévesque ◽

Massimo Avoli

Keyword(s):

Potassium Chloride ◽

Entorhinal Cortex ◽

Single Unit ◽

Neuronal Excitability ◽

Cell Activity ◽

Principal Cell ◽

Cell Firing ◽

Interictal Discharges ◽

Tetrode Recordings

The potassium-chloride cotransporter 2 (KCC2) plays a role in epileptiform synchronization, but it remains unclear how it influences such a process. Here, we used tetrode recordings in the in vitro rat entorhinal cortex (EC) to analyze the effects of the KCC2 antagonist VU0463271 on 4-aminopyridine (4AP)-induced ictal and interictal activity. During 4AP application, ictal events were associated with significant increases in interneurons and principal cells activities. VU0463271 application transformed ictal discharges to shorter ictal-like events that were not accompanied by significant increases in interneuron or principal cell firing. Interictal events persisted during VU0463271 application at an accelerated frequency of occurrence with significant increases in interneuron and principal cell activity. Further analysis revealed that interneuron and principal cell firing rate during 4AP-induced interictal events were increased after VU0463271 application without changes in synchronicity. Overall, our results demonstrate that in the EC, KCC2 antagonism enhances both interneuron and principal cell excitability, while paradoxically decreasing the ability of neuronal networks to generate structured ictal events. NEW & NOTEWORTHY We are the first to use tetrode recordings in the entorhinal cortex to demonstrate that antagonizing potassium-chloride cotransporter 2 (KCC2) function abolishes ictal discharges and the associated, dynamic changes in single-unit firing in the in vitro 4-aminopyrine model of epileptiform synchronization. Interictal discharges were, however, shorter and more frequent during KCC2 antagonism, while the associated single-unit activity increased, suggesting augmented neuronal excitability. Our findings highlight the complex role of KCC2 in disease pathology.

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Effects of 17β-estradiol on glutamate synaptic transmission and neuronal excitability in the rat medial vestibular nuclei

Neuroscience ◽

10.1016/j.neuroscience.2009.11.039 ◽

2010 ◽

Vol 165 (4) ◽

pp. 1100-1114 ◽

Cited By ~ 28

Author(s):

S. Grassi ◽

A. Frondaroli ◽

M. Scarduzio ◽

M.B. Dutia ◽

C. Dieni ◽

...

Keyword(s):

Synaptic Transmission ◽

Neuronal Excitability ◽

Vestibular Nuclei ◽

17Β Estradiol

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Dopaminergic Regulation of Neuronal Excitability through Modulation of Ih in Layer V Entorhinal Cortex

Journal of Neuroscience ◽

10.1523/jneurosci.4333-05.2006 ◽

2006 ◽

Vol 26 (12) ◽

pp. 3229-3244 ◽

Cited By ~ 66

Author(s):

J. A. Rosenkranz

Keyword(s):

Entorhinal Cortex ◽

Neuronal Excitability ◽

Layer V ◽

Dopaminergic Regulation

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Contribution of near-threshold currents to intrinsic oscillatory activity in rat medial entorhinal cortex layer II stellate cells

Journal of Neurophysiology ◽

10.1152/jn.00743.2011 ◽

2013 ◽

Vol 109 (2) ◽

pp. 445-463 ◽

Cited By ~ 24

Author(s):

Anne Boehlen ◽

Christian Henneberger ◽

Uwe Heinemann ◽

Irina Erchova

Keyword(s):

Entorhinal Cortex ◽

Neuronal Excitability ◽

Spatial Information ◽

Sodium Current ◽

Stellate Cells ◽

Frequency Component ◽

Oscillatory Activity ◽

Potential Oscillations ◽

Near Threshold

The temporal lobe is well known for its oscillatory activity associated with exploration, navigation, and learning. Intrinsic membrane potential oscillations (MPOs) and resonance of stellate cells (SCs) in layer II of the entorhinal cortex are thought to contribute to network oscillations and thereby to the encoding of spatial information. Generation of both MPOs and resonance relies on the expression of specific voltage-dependent ion currents such as the hyperpolarization-activated cation current ( IH), the persistent sodium current ( INaP), and the noninactivating muscarine-modulated potassium current ( IM). However, the differential contributions of these currents remain a matter of debate. We therefore examined how they modify neuronal excitability near threshold and generation of near-threshold MPOs and resonance in vitro. We found that resonance mainly relied on IH and was reduced by IH blockers and modulated by cAMP and an IM enhancer but that neither of the currents exhibited full control over MPOs in these cells. As previously reported, IH controlled a theta-frequency component of MPOs such that blockade of IH resulted in fewer regular oscillations that retained low-frequency components and high peak amplitude. However, pharmacological inhibition and augmentation of IM also affected MPO frequencies and amplitudes. In contrast to other cell types, inhibition of INaP did not result in suppression of MPOs but only in a moderation of their properties. We reproduced the experimentally observed effects in a single-compartment stochastic model of SCs, providing further insight into the interactions between different ionic conductances.

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