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1.
Epilepsy Res ; 157: 106196, 2019 11.
Article in English | MEDLINE | ID: mdl-31499340

ABSTRACT

In the immature brain the neurotransmitter γ-amino butyric acid (GABA) mediates a membrane depolarization and can contribute to both, inhibition and excitation. Therefore the consequences of a positive modulation of GABA(A) receptors by neurosteroids on epileptiform activity are hard to predict. In order to analyze whether neurosteroids attenuate or exaggerate epileptiform activity in the immature brain, we investigated the effect of the neurosteroid allopregnanolone on epileptiform activity in an in-toto hippocampus preparation of early postnatal mice (postnatal days 4-7) using field potential recordings. These in-vitro experiments revealed that 0.5 µmol/L allopregnanolone had no effect on ictal-like epileptiform activity, but increased the occurrence of interictal epileptiform events. The allopregnanolone-induced enhancement of interictal epileptiform activity could be blocked by a selective inhibition of synaptic GABAA receptors. In contrast, allopregnanolone had no effect on interictal epileptiform activity upon enhanced extrasynaptic GABAergic activity. Patch-clamp experiments demonstrated that allopregnanolone prolonged the decay of GABAergic postsynaptic currents, but had no effect on tonic GABAergic currents. We conclude from these results that allopregnanolone can enhance excitability in the immature hippocampus viaprolonged synaptic GABAergic currents. This potential effect of neurosteroids on brain excitability should be considered if they are applied as anticonvulsants to premature or early postnatal babies.


Subject(s)
Hippocampus/drug effects , Membrane Potentials/drug effects , Pregnanolone/pharmacology , Animals , GABA-A Receptor Antagonists/pharmacology , Mice , Patch-Clamp Techniques , Picrotoxin/pharmacology
2.
EMBO Rep ; 20(6)2019 06.
Article in English | MEDLINE | ID: mdl-30948457

ABSTRACT

Learning is essential for survival and is controlled by complex molecular mechanisms including regulation of newly synthesized mRNAs that are required to modify synaptic functions. Despite the well-known role of RNA-binding proteins (RBPs) in mRNA functionality, their detailed regulation during memory consolidation is poorly understood. This study focuses on the brain function of the RBP Gadd45α (growth arrest and DNA damage-inducible protein 45 alpha, encoded by the Gadd45a gene). Here, we find that hippocampal memory and long-term potentiation are strongly impaired in Gadd45a-deficient mice, a phenotype accompanied by reduced levels of memory-related mRNAs. The majority of the Gadd45α-regulated transcripts show unusually long 3' untranslated regions (3'UTRs) that are destabilized in Gadd45a-deficient mice via a transcription-independent mechanism, leading to reduced levels of the corresponding proteins in synaptosomes. Moreover, Gadd45α can bind specifically to these memory-related mRNAs. Our study reveals a new function for extended 3'UTRs in memory consolidation and identifies Gadd45α as a novel regulator of mRNA stability.


Subject(s)
Cell Cycle Proteins/metabolism , Gene Expression Regulation , Learning , Memory , RNA, Messenger/genetics , Amygdala/metabolism , Animals , Behavior, Animal , Cell Cycle Proteins/genetics , Gene Expression , Hippocampus/metabolism , Mice , Mice, Knockout , Neuronal Plasticity/genetics , Pain Threshold , RNA Interference
3.
Elife ; 62017 08 21.
Article in English | MEDLINE | ID: mdl-28826501

ABSTRACT

Programmed cell death widely but heterogeneously affects the developing brain, causing the loss of up to 50% of neurons in rodents. However, whether this heterogeneity originates from neuronal identity and/or network-dependent processes is unknown. Here, we report that the primary motor cortex (M1) and primary somatosensory cortex (S1), two adjacent but functionally distinct areas, display striking differences in density of apoptotic neurons during the early postnatal period. These differences in rate of apoptosis negatively correlate with region-dependent levels of activity. Disrupting this activity either pharmacologically or by electrical stimulation alters the spatial pattern of apoptosis and sensory deprivation leads to exacerbated amounts of apoptotic neurons in the corresponding functional area of the neocortex. Thus, our data demonstrate that spontaneous and periphery-driven activity patterns are important for the structural and functional maturation of the neocortex by refining the final number of cortical neurons in a region-dependent manner.


Subject(s)
Apoptosis , Cerebral Cortex/cytology , Cerebral Cortex/physiology , Electrophysiological Phenomena , Neurons/cytology , Aging/physiology , Anesthesia , Animals , Animals, Newborn , Caspase 3/metabolism , Cell Count , Cerebral Cortex/embryology , Mice , Motor Cortex/physiology , Neurons/metabolism , Somatosensory Cortex/physiology
4.
J Physiol ; 592(10): 2153-68, 2014 May 15.
Article in English | MEDLINE | ID: mdl-24665103

ABSTRACT

While the expression of glycine receptors in the immature hippocampus has been shown, no information about the role of glycine receptors in controlling the excitability in the immature CNS is available. Therefore, we examined the effect of glycinergic agonists and antagonists in the CA3 region of an intact corticohippocampal preparation of the immature (postnatal days 4-7) rat using field potential recordings. Bath application of 100 µM taurine or 10 µM glycine enhanced the occurrence of recurrent epileptiform activity induced by 20 µM 4-aminopyridine in low Mg(2+) solution. This proconvulsive effect was prevented by 3 µM strychnine or after incubation with the loop diuretic bumetanide (10 µM), suggesting that it required glycine receptors and an active NKCC1-dependent Cl(-) accumulation. Application of higher doses of taurine (≥ 1 mM) or glycine (100 µM) attenuated recurrent epileptiform discharges. The anticonvulsive effect of taurine was also observed in the presence of the GABAA receptor antagonist gabazine and was attenuated by strychnine, suggesting that it was partially mediated by glycine receptors. Bath application of the glycinergic antagonist strychnine (0.3 µM) induced epileptiform discharges. We conclude from these results that in the immature hippocampus, activation of glycine receptors can mediate both pro- and anticonvulsive effects, but that a persistent activation of glycine receptors is required to suppress epileptiform activity. In summary, our study elucidated the important role of glycine receptors in the control of neuronal excitability in the immature hippocampus.


Subject(s)
Epilepsy/physiopathology , Glycine/administration & dosage , Hippocampus/physiopathology , Receptors, Glycine/agonists , Receptors, Glycine/metabolism , Taurine/administration & dosage , Animals , Animals, Newborn , Anticonvulsants/administration & dosage , Cells, Cultured , Epilepsy/drug therapy , Hippocampus/drug effects , Rats , Rats, Wistar
5.
Epilepsy Res ; 108(2): 182-9, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24359690

ABSTRACT

GABA transporters (GATs) are an essential element of the GABAergic system, which regulate excitability in the central nervous system and are thus used as targets for anticonvulsive therapy. However, in the immature nervous system the functions of the GABAergic system and the expression profile of GATs are distinct from the adult situation, obscuring to predict how different GAT isoforms influence epileptiform activity. Therefore we analyzed the effects of subtype specific GAT inhibitors on repetitive epileptiform discharges using field potential and whole-cell patch-clamp recordings in the CA3 region of hippocampal slices of immature (postnatal days 4-7) rats. These experiments revealed that inhibition of GAT-1 with either tiagabine (30 µM) or NO-711 (10 µM) exhibited only a minor anticonvulsive effect on repetitive epileptiform discharges. Blockade of GAT-2/3 with SNAP-5114 (40 µM) had no anticonvulsive effect, but significantly prolonged the decay of spontaneous GABAergic postsynaptic currents. In contrast, the combined application of 10 µM NO-711 and 40 µM SNAP-5114 blocked epileptiform activity in 33% of all slices and reduced the occurrence of epileptiform discharges by 54% in the remaining slices. In addition, the input resistance decreased by 10.5 ± 1.0% under this condition. These results indicate that both GAT-1 and GAT-2/3 are functional in the immature hippocampus and that only the combined inhibition of GAT 1-3 is sufficient to promote a considerable anticonvulsive effect. We conclude from these results that both GAT-1 and GAT-2/3 act synergistically to regulate the excitability in the immature hippocampus.


Subject(s)
4-Aminopyridine/toxicity , CA3 Region, Hippocampal/growth & development , CA3 Region, Hippocampal/physiopathology , GABA Antagonists/pharmacology , GABA Plasma Membrane Transport Proteins/physiology , GABA Uptake Inhibitors/pharmacology , Neural Inhibition/physiology , 4-Aminopyridine/administration & dosage , Action Potentials/drug effects , Action Potentials/physiology , Animals , Animals, Newborn , CA3 Region, Hippocampal/drug effects , GABA Antagonists/therapeutic use , GABA Plasma Membrane Transport Proteins/metabolism , Male , Neural Inhibition/drug effects , Organ Culture Techniques , Rats , Rats, Wistar , Seizures/drug therapy , Seizures/physiopathology
6.
J Physiol ; 590(19): 4717-33, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22826132

ABSTRACT

Neuroplastic changes at the spinal synapses between primary nociceptors and second order dorsal horn neurons play key roles in pain and analgesia. NMDA receptor-dependent forms of long-term plasticity have been studied extensively at these synapses, but little is known about possible contributions of the endocannabinoid system. Here, we addressed the role of cannabinoid (CB)1 receptors in activity-dependent plasticity at these synapses. We report that conditional low-frequency stimulation of high-threshold primary sensory nerve fibres paired with depolarisation of the postsynaptic neuron evoked robust long-term depression (LTD)of excitatory synaptic transmission by about 40% in the vast majority (90%) of recordings made in wild-type mice. When recordings were made from global or nociceptor-specific CB(1) receptor-deficient mice (CB(1) (−/− ) mice and sns-CB(1)(−/−) mice), the portion of neurons exhibiting LTD was strongly reduced to about 25%. Accordingly, LTD was prevented to a similar extent by the CB1 receptor antagonist AM251 and mimicked by pharmacological activation of CB1 receptors. In a subset of neurons with EPSCs of particularly high stimulation thresholds, we furthermore found that the absence of CB(1) receptors in CB(1)(−/−) and sns-CB(1)(−/−) mice converted the response to the paired conditioning stimulation protocol from LTD to long-term potentiation (LTP). Our results identify CB1 receptor-dependent LTD as a form of synaptic plasticity previously unknown in spinal nociceptors. They furthermore suggest that prevention of LTP may be a second hither to unknown function of CB1 receptors in primary nociceptors. Both findings may have important implications for our understanding of endogenous pain control mechanisms and of analgesia evoked by cannabinoid receptor agonists.


Subject(s)
Neuronal Plasticity/physiology , Receptor, Cannabinoid, CB1/physiology , Spinal Cord/physiology , Animals , Endocannabinoids/physiology , Excitatory Postsynaptic Potentials , Female , In Vitro Techniques , Male , Mice , Mice, Transgenic , Nociceptors/physiology , Synapses/physiology
7.
J Neurosci Res ; 90(10): 2020-33, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22714119

ABSTRACT

To investigate whether epileptiform activity in the immature brain is modulated by dopamine, we examined the effects of dopaminergic agonists and antagonists in an intact in vitro preparation of the isolated corticohippocampal formation of immature (postnatal days 3 and 4) C57/Bl6 mice using field potential recordings from CA3. Epileptiform discharges were induced by a reduction of the extracellular Mg(2+) concentration to 0.2 mM. These experiments revealed that low concentrations of dopamine (<0.3 µM) attenuated epileptiform activity, whereas >3 µM dopamine enhanced epileptiform activity. The D1-agonist SKF38393 (10 µM) had a strong proconvulsive effect, and the D2-like agonist quinpirole (10 µM) mediated a weak anticonvulsive effect. The proconvulsive effect of 10 µM dopamine was completely abolished by the D1-like receptor antagonist SCH39166 (2 µM) or the D2-like antagonist sulpiride (10 µM), whereas the D2 antagonist L-741626 (50 nM) and the D3 antagonist SB-277011-A (0.1 µM) were without effect. The anticonvulsive effect of 0.1 µM dopamine could be suppressed by D1-like, D2, or D3 receptor antagonists. A proconvulsive effect of 10 µM dopamine was also observed when AMPA, NMDA, or GABA(A) receptors were blocked. In summary, these results suggest that 1) dopamine influences epileptiform activity already at early developmental stages; 2) dopamine can bidirectionally influence the excitability; 3) D1-like receptors mediate the proconvulsive effect of high dopamine concentrations, although the pharmacology of the anticonvulsive effect is less clear; and 4) dopamine-induced alterations in GABAergic and glutamatergic systems may contribute to this effect.


Subject(s)
Dopamine/physiology , Epilepsy/physiopathology , Hippocampus/physiopathology , Magnesium Deficiency/physiopathology , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Animals, Newborn , Benzazepines/pharmacology , Data Interpretation, Statistical , Dopamine/pharmacology , Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Indoles/pharmacology , Mice , Mice, Inbred C57BL , Nitriles/pharmacology , Piperidines/pharmacology , Quinpirole/pharmacology , Receptors, Dopamine D2/agonists , Synapses/drug effects , Tetrahydroisoquinolines/pharmacology
8.
Epilepsia ; 53(5): 888-96, 2012 May.
Article in English | MEDLINE | ID: mdl-22432890

ABSTRACT

PURPOSE: Despite the consistent observation that γ-aminobutyric acid A (GABA(A) ) receptors mediate excitatory responses at perinatal stages, the role of the GABAergic system in the generation of neonatal epileptiform activity remains controversial. Therefore, we analyzed whether tonic and phasic GABAergic transmission had differential effects on neuronal excitability during early development. METHODS: We performed whole cell patch-clamp and field potential recordings in the CA3 region of hippocampal slices from immature (postnatal day 4-7) rats to analyze the effect of specific antagonists and modulators of tonic and phasic GABAergic components on neuronal excitability. KEY FINDINGS: The GABAergic antagonists gabazine (3 µm) and picrotoxin (100 µm) induced epileptiform discharges, whereas activation of GABA(A) receptors attenuated epileptiform discharges. Under low-Mg(2+) conditions, 100 nm gabazine and 1 µm picrotoxin were sufficient to provoke epileptiform activity in 63.2% (n = 19) and 53.8% (n = 26) of the slices, respectively. Whole-cell patch-clamp experiments revealed that these concentrations significantly reduced the amplitude of phasic GABAergic postsynaptic currents but had no effect on tonic currents. In contrast, 1-µm 4,5,6,7-tetrahydroisoxaz-olo[5,4-c]-pyridin-3-ol (THIP) induced a tonic current of -12 ± 2.5 pA (n = 6) and provoked epileptiform discharges in 57% (n = 21) of the slices. SIGNIFICANCE: We conclude from these results that in the early postnatal rat hippocampus a constant phasic synaptic activity is required to control excitability and prevent epileptiform activity, whereas tonic GABAergic currents can mediate excitatory responses. Pharmacologic intervention at comparable human developmental stages should consider these ambivalent GABAergic actions.


Subject(s)
Action Potentials/physiology , CA3 Region, Hippocampal/physiology , Pyridazines/pharmacology , Receptors, GABA-A/metabolism , Action Potentials/drug effects , Age Factors , Animals , Animals, Newborn , Biophysical Phenomena/drug effects , CA3 Region, Hippocampal/drug effects , CA3 Region, Hippocampal/growth & development , Convulsants/pharmacology , Electric Stimulation , GABA Antagonists/pharmacology , In Vitro Techniques , Inhibitory Postsynaptic Potentials/drug effects , Patch-Clamp Techniques , Picrotoxin/pharmacology , Rats , Rats, Wistar , Sodium Channel Blockers/pharmacology , Tetrodotoxin/pharmacology , gamma-Aminobutyric Acid/pharmacology
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