Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “iPSC”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed2026

Human iPSC-EV-loaded nanofiber stent coatings accelerate vascular repair by enhancing EGFR/HIF-1α signaling and suppressing ROCK1-mediated remodeling.

Arterial disease management is shifting from antiproliferative drug-eluting stents toward approaches that restore endothelial function and modulate smooth muscle cell (SMC) behavior. Stem cell-derived extracellular vesicles (EVs) carry miRNAs that promote endothelial proliferation and migration while restraining aberrant SMC growth and inflammation. Here, human induced pluripotent stem cell (iPSC)-derived EVs were collected by ultracentrifugation and incorporated into 50:50 poly (lactic-co-glycolic acid) (PLGA 503) core-shell nanofibrous membranes, which were fabricated as stent coatings for sustained release to overcome rapid clearance and poor tissue retention. EVs derived from three independent iPSC lines all enhanced tube formation in human umbilical vein endothelial cells (HUVECs) under hypoxic and serum-starved conditions and revealed a trend toward reduced platelet-derived growth factor-BB (PDGF-BB)-induced smooth muscle cell (SMC) migration. The fabricated core-shell nanofibers enabled sustained EV release, maintaining therapeutic efficacy for 28 days. Small RNA sequencing (NGS) analysis demonstrated that EVs from these independent iPSC lines shared miR-148a-3p and members of the miR-92 family, which collectively accounted for more than 75% of the reads within the 25 top-expressed miRNA set. In vitro, iPSC-EVs enhanced HUVEC proliferation and survival signaling by downregulating the negative regulators ERRFI1 and VHL, which are specific targets of miR-148a-3p and the miR-92 family, thereby activating the EGFR and HIF-1α axes and driving downstream ERK1/2 and VEGF expression under hypoxic and serum starvation stress conditions. Concurrently, iPSC-EVs prevented PDGF-BB-induced SMC phenotypic switching by downregulating ROCK1, a target of miR-148a-3p, thereby inhibiting downstream AKT and ERK signaling and preserving contractile markers while suppressing the synthetic phenotype. In vivo, the iPSC-EV-functionalized scaffolds significantly accelerated re-endothelialization and inhibited neointimal hyperplasia, evidenced by the upregulation of angiogenic factors (VEGF, CD31) and the concurrent suppression of pathological remodeling markers (α-SMA, MMPs) and inflammatory cytokines (IL-6, TGF-β1). Therefore, iPSC-EVs enriched with specific miRNAs and delivered via PLGA 503 core-shell nanofibers promote endothelial repair while suppressing SMC overgrowth, providing a promising strategy for vascular healing.

Core-shell nanofibers↗
PubMed2026

Fetal signatures in the 3D genome of iPSC-derived neurons and their implications for disease modeling.

Induced pluripotent stem cells (iPSCs) have revolutionized neuroscience, providing an approach to generate patient-specific neurons for modeling of neurological diseases. However, it remains unclear how closely iPSC-derived neurons replicate the chromatin architecture of authentic brain neurons. Here, we uniformly processed newly generated Hi-C data from iPSC-derived neurons and neurons isolated from the human postmortem brain, together with previously published data sets comprising 228 human and 89 mouse Hi-C and snm3C-seq samples from different cell subtypes. These data were merged into 96 high-coverage contact maps used to examine chromatin features ranging from chromatin compartments and topologically associating domains (TADs) to chromatin loops, Polycomb-mediated contacts, and frequently interacting regions (FIREs). We find that iPSC-derived neurons largely retain the chromatin state of undifferentiated cells and resemble fetal rather than mature neurons. iPSC-derived neurons exhibit unusually strong compartmentalization, an enrichment of developmental genes at TAD borders, and a marked reduction of long-range repressive Polycomb-mediated contacts that typically silence early fetal programs. Although immature, iPSC-derived neurons offer advantages for modeling interactions between disease-associated SNPs and target genes, as many psychiatric disorders have neurodevelopmental origins. Integrating iPSC-derived and postmortem neuronal data sets therefore provides complementary insights into the chromatin landscape underlying disease-associated interactions. Our study offers a valuable Hi-C resource for the community and provides a detailed comparison of chromatin architecture throughout neuronal maturation, underscoring its importance for validating neuronal models and providing a robust framework for future studies.

Journal Article↗
PubMed1997

Inhibition of spontaneous EPSCs and IPSCs by presynaptic GABAB receptors on rat supraoptic magnocellular neurons.

1. The function of presynaptic GABA receptors in the regulation of transmitter release in supraoptic nucleus (SON) magnocellular neurons was investigated by recording spontaneous postsynaptic currents from rat magnocellular SON neurons in a slice preparation (150 microns thick, 1.8 mm in diameter) using the whole-cell patch-clamp technique. 2. Both the spontaneous EPSCs and IPSCs were TTX resistant. The EPSCs were abolished by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), whereas the IPSCs were abolished by picrotoxin, suggesting that the EPSCs and IPSCs are synaptic inputs from glutamatergic and GABAergic neurons, respectively. 3. The selective GABAB agonist, baclofen, reduced the frequency of both the EPSCs and IPSCs without affecting the amplitude. The time constant of the decay phase of both the EPSCs and IPSCs remained unchanged after baclofen application. 4. The reduction of the frequency of the synaptic currents by baclofen was dose dependent (10 nM to 100 microM) and the EC50 values were 5.8 and 8.5 microM for the EPSCs and IPSCs, respectively. 5. The effect of baclofen (10 microM) was antagonized by the selective GABAB antagonist, 2-hydroxy-saclofen (2OH-saclofen), at 300 microM. 6. When given alone, 2OH-saclofen (100 microM) increased the frequency of both the EPSCs and IPSCs without affecting their amplitude, suggesting that endogenously released GABA in the slice acts on presynaptic GABAB receptors. 7. The GABAA agonist, muscimol, reduced the frequency of EPSCs, and picrotoxin increased the frequency of the EPSCs, suggesting that GABAA receptors also participate in the presynaptic inhibition of glutamate release. 8. Taken together, these data suggest that GABAB receptors are present on the presynaptic terminals of both GABA and glutamate neurons in the SON, and that these presynaptic GABAB receptors play an important role in the regulation of the neuronal activity in SON magnocellular neurons.

Animals↗
PubMed2003

Parvalbumin-deficiency facilitates repetitive IPSCs and gamma oscillations in the hippocampus.

In the hippocampus, the calcium-binding protein parvalbumin (PV) is expressed in interneurons that innervate perisomatic regions. PV in GABAergic synaptic terminals was proposed to limit repetitive GABA release by buffering of "residual calcium." We assessed the role of presynaptic PV in Ca(2+)-dependent GABA release in the hippocampus of PV-deficient (PV-/-) mice and wild-type (PV+/+) littermates. Pharmacologically isolated inhibitory postsynaptic currents (IPSCs) were evoked by low-intensity stimulation of the stratum pyramidale and recorded from voltage-clamped CA1 pyramidal neurons. The amplitude and decay time constant of single IPSCs were similar for both genotypes. Under our experimental conditions of reduced release probability and minimal presynaptic suppression, paired-pulse facilitation of IPSCs occurred at intervals from 2 to 50 ms, irrespective of the presence of PV. The facilitation of IPSCs induced by trains of 10 stimuli at frequencies >20 Hz was enhanced in cells from PV-/- mice, the largest difference between PV-/- and PV+/+ animals (220%) being observed at 33 Hz. The effect of IPSC facilitation at sustained gamma frequencies was assessed on kainate-induced rhythmic IPSC-paced neuronal oscillations at gamma frequencies, recorded with dual field potential recordings in area CA3. The maximum power of the oscillation was 138 microV(2) at 36 Hz in slices from PV+/+ mice and was trebled in slices from PV-/- mice. PV deficiency caused a similar increase in gamma power under conditions used to study IPSC facilitation and can be explained by an increased facilitation of GABA release at sustained high frequencies. The dominant frequency and coherence were not affected by PV deficiency. These observations suggest that PV deficiency, due to an increased short-term facilitation of GABA release, enhances inhibition by high-frequency burst-firing PV-expressing interneurons and may affect the higher cognitive functions associated with gamma oscillations.

Animals↗
PubMed1994

Factors contributing to the decay of the stimulus-evoked IPSC in rat hippocampal CA1 neurons.

1. Monosynaptic gamma-aminobutyric acid-A (GABAA)-mediated inhibitory postsynaptic currents (IPSCs) were evoked in CA1 pyramidal neurons in the hippocampal slice preparation by direct stimulation of the interneurons in the presence of glutamatergic blockers and intracellular QX-314 to block GABAB-mediated postsynaptic inhibition. 2. Paired-pulse stimulation was used to activate presynaptic GABAB autoreceptors and thereby reduce the amount of transmitter release. This caused paired-pulse depression, persisting for > 3 s, and maximal at interpulse intervals between 100 and 250 ms where peak current (Ipeak) was decreased by 29.7% and decay time (t1/2) was decreased by 44.7%. There was clear correlation between changes in Ipeak and t1/2 at all interpulse intervals. 3. With paired-pulse stimulation, the decay of the second IPSC in most cells (12/18) could be resolved into two components, Ifast and Islow, each decaying monoexponentially with tau fast = 14.10 ms and tau slow = 58.87 ms. The faster decay during paired-pulse depression was predominantly caused by a larger Ifast fraction, which accounted for 27.5% of Ipeak in a single control IPSC and 79.3% at an interpulse interval of 250 ms. 4. Reducing the probability for transmitter release at all active sites by reducing [Ca2+]o from 2 mM to 1 mM decreased Ipeak by 49.7%, reduced paired-pulse depression, and partly mimicked the changes in decay kinetics seen after activation of presynaptic GABAB receptors. Lowering the stimulating intensity to 10% of the maximal value decreased Ipeak by 73.8%, but hardly affected the decay of the IPSC and the paired-pulse depression. 5. Application of the selective blocker of GABA uptake, tiagabine (20-50 microM), increased t1/2 of a single IPSC by 114% without affecting Ipeak. The increase was caused solely by an increase in tau slow of 141%. On the other hand, the benzodiazepine agonist midazolam (2 microM), selectively increased tau fast. It therefore is suggested that tau fast reflects the kinetics of the GABAA receptor/ionophore complex and tau slow the efficiency of the GABA uptake system. 6. The findings show that GABA activates postsynaptic receptors throughout the tail of a single IPSC. This could be caused by reactivation of synaptic receptors or activation of extrasynaptic receptors. The decay therefore is limited mainly by the efficiency of the uptake system. An IPSC that is maximally depressed by paired-pulse stimulation is mediated primarily by a single activation of synaptic receptors, and the decay is limited mainly by the kinetics of the GABAA receptor/ionophore complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2025

The role of iPSC research for insight into inherited arrhythmia conditions.

Human induced pluripotent stem cells (iPSCs) have emerged as a transformative platform for modeling inherited cardiac arrhythmia syndromes and uncovering human-specific disease mechanisms. However, the promise of iPSC-derived cardiomyocytes lies beyond the recapitulation of arrhythmogenic phenotypes and channelopathies. In this review, we explore recent works which have enabled mechanistic interrogation and therapeutic insight for inherited arrhythmia syndromes, beyond the capabilities of traditional animal models. Such studies have leveraged iPSCs to elucidate the role of splice variants, transcriptional regulation, and mitochondrial stress in arrhythmogenesis. Further, iPSC systems have proven important for reclassifying variants of uncertain significance and in modeling idiopathic arrhythmias where genotype-phenotype links are elusive. Advances in directed differentiation now permit chamber-specific cardiac cell generation, allowing for atrial and ventricular disease modeling and revealing critical cell-cell interactions. iPSCs also serve as high-fidelity precursor platforms for drug testing, offering predictive insight into mutation-specific responses to pharmacologic and genetic therapies. Though limitations in maturation and scalability persist, ongoing efforts for integration with tissue engineering, multi-cellular models, and computational frameworks are evolving to improve model reliability. iPSC-based systems now occupy a critical role in arrhythmia research, bridging basic discovery with translational applications, thereby contributing to personalizing care and advancing therapeutics in inherited and idiopathic arrhythmic syndromes.

Humans↗
PubMed2004

5-Hydroxytryptamine 1B receptors mediate presynaptic inhibition of monosynaptic IPSC in the rat dorsolateral septal nucleus.

Effects of 5-hydroxytryptamine (5-HT) on inhibitory synaptic transmission in the rat dorsolateral septal nucleus (DLSN) were examined by conventional intracellular and voltage-clamp recording methods. 5-HT (1-30 microM) depressed the monosynaptic fast IPSC evoked by local stimulation of the DLSN in the presence of DNQX, AP5 and CGP 55845A. CP 93129, a selective 5-HT1B receptor agonist, depressed the fast IPSC. The 5-HT-induced depression of the fast IPSC was attenuated by SB 216641, a selective antagonist for 5-HT1B receptors. 5-HT did not change the inward currents mediated by GABAA receptors, suggesting that 5-HT presynaptically inhibited the fast IPSC. 5-HT and CP 93129 depressed the frequency of miniature fast IPSPs (mIPSPs) without changing their amplitudes. Neither a selective protein kinase A inhibitor, H-89, nor a selective protein kinase C inhibitor, calphostin C, blocked the 5-HT-induced depression of the fast IPSC. N-Ethylmaleimide (NEM) blocked the 5-HT-induced depression of the evoked IPSC. These results suggest that activation of presynaptic 5-HT1B receptors depresses the release of GABA via a pertussis toxin (PTX)-sensitive G-protein in the rat DLSN.

Analysis of Variance↗
PubMed1998

Modulation of inhibitory post-synaptic currents (IPSCs) in mouse cerebellar Purkinje and basket cells by snake and scorpion toxin K+ channel blockers.

Using an in vitro mouse cerebellar slice preparation and whole-cell electrophysiological recording techniques we have characterized Purkinje and basket cell inhibitory post-synaptic currents (IPSCs), and examined the effects of a number of selective peptidergic K+ channel blockers. Spontaneous IPSC amplitude ranged from approximately 10 pA up to approximately 3 nA for both cell types [mean values: Purkinje cells -122.8+/-20.0 pA (n = 24 cells); basket cells -154.8+/-15.9 pA (n = 26 cells)]. Frequency varied from approximately 3 up to approximately 40 Hz, [mean values: basket cells 14.9+/-1.7 Hz (n=26 cells); Purkinje cells 17.9+/-2.2 Hz (n=24 cells)]. 5 microM bicuculline eliminated virtually all spontaneous currents. IPSC rise times were fast (approximately 0.6 ms) and the decay phase was best fit with the sum of two exponential functions (tau1 and tau2: approximately 4 ms and approximately 20 ms, n=40; for both cell types). The snake toxins alpha-dendrotoxin (alpha-DTX) and toxin K greatly enhanced IPSC frequency and amplitude in both cell types; the closely related homologues toxin I and gamma-dendrotoxin (gamma-DTX) produced only marginal enhancements (all at 200 nM). Two scorpion toxins, margatoxin (MgTX) and agitoxin-2 (AgTX-2) had only minor effects on IPSC frequency or amplitude (both at 10 nM). Low concentrations of tetraethylammonium (TEA; 200 microM) had no overall effect on cerebellar IPSCs, whilst higher concentrations (10 mM) increased both the frequency and amplitude. The results suggest that native K+ channels, containing Kv1.1 and Kv1.2 channel subunits, play an influential role in controlling GABAergic inhibitory transmission from cerebellar basket cells.

Animals↗
PubMed1999

Dual actions of volatile anesthetics on GABA(A) IPSCs: dissociation of blocking and prolonging effects.

BACKGROUND: Volatile agents alter inhibitory postsynaptic currents (IPSCs) at clinically relevant concentrations, an action that is thought to make an important contribution to their behavioral effects. The authors investigated the mechanisms underlying these effects by evaluating the concentration dependence of modulation by enflurane, isoflurane, and halothane of IPSCs in rat hippocampal slices. METHODS: Action potential-independent gamma-aminobutyric acid(A) IPSCs (miniature IPSCs [mIPSCs]) were recorded from CA1 pyramidal neurons. The effects on mIPSC amplitude were used to distinguish between presynaptic (altered release) and postsynaptic (altered receptor response) actions of volatile agents. The concentration dependence of blocking and prolonging actions was compared among the volatile agents to determine whether a single modulatory process could account for both effects. RESULTS: The application of volatile anesthetics prolonged the decay and reduced the amplitude of mIPSCs in a dose-dependent manner. The effects on decay time for isoflurane and enflurane could not be distinguished. However, the blocking effect of enflurane was significantly greater than that of isoflurane at all concentrations. Despite the blocking effect, the net action of these agents was enhanced inhibition, because charge transfer was always significantly greater than control. Isoflurane, and to a lesser extent enflurane and halothane, caused a picrotoxin-sensitive increase in baseline noise. Moderate increases in mIPSC frequency were also observed for all agents. CONCLUSIONS: These results show that enflurane, isoflurane, and halothane reduce IPSC amplitude through a direct postsynaptic action. Furthermore, the concentration dependence of the actions of the agents reveals a dissociation between the effects on the amplitude and the time course of IPSCs, suggesting that distinct mechanisms underlie the two actions.

Algorithms↗
PubMed1996

Potentiation of IPSCs by nitric oxide in immature rat sympathetic preganglionic neurones in vitro.

1. Whole-cell patch-clamp recording techniques were applied to sympathetic preganglionic neurones (SPNs), the majority of which contain neuronal nitric oxide synthase (NOS), in transverse thoracolumbar spinal cord slices from 8- to 12-day-old rats, and the role of nitric oxide (NO) in modulating the inhibitory postsynaptic current (IPSC) evoked by focal stimulation was examined. 2. Superfusing the slices with the NO precursor L-arginine (L-Arg, 300 microM) and the NO donor sodium nitroprusside (SNP, 100 microM) potentiated IPSCs from several minutes to more than 1 h; the increase was prevented by pretreating the slices with bovine haemoglobin (100 microM), the nitric oxide synthase inhibitor N omega-nor-L-arginine (NO-Arg, 100 microM) or the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 microM). Haemoglobin, NO-Arg and ODQ slightly reduced the IPSCs evoked in some of the SPNs. 3. Superfusion of the slices with N2,2'-O-dibutyrylguanosine 3',5'-cyclic monophosphate (dbcGMP, 300 microM) in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 750 microM) reversibly increased the IPSCs as well. 4. While enhancing the IPSCs, L-Arg or SNP had no significant effects on outward currents induced by pressure application of the putative inhibitory transmitter glycine in the same cells. 5. A train of suprathreshold depolarizing current pulses (30 Hz for 10 s) injected into the recording SPNs caused, after a delay of several minutes, a long-lasting increase of IPSCs; this effect was nullified by superfusing the slices with haemoglobin or NO-Arg. 6. The result suggests that NO released endogenously from SPNs may act as a retrograde messenger molecule to enhance the release of glycine or a related substance, possibly via a cGMP-dependent mechanism.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Activation of presynaptic GABAB receptors inhibits evoked IPSCs in rat magnocellular neurons in vitro.

1508-1517, 1998. Whole cell recordings (nystatin-perforated patch) were carried out on magnocellular neurons of the rat supraoptic nucleus (SON) to study the modulation of inhibitory postsynaptic currents (IPSCs) by gamma-aminobutyric acid-B (GABAB) receptors. Field stimulation adjacent to the SON in the presence of kynurenic acid, evoked monosynaptic GABAergic IPSCs. Baclofen reversibly reduced the amplitude of the IPSCs in a dose-dependent manner (EC50: 0.68 microM) without apparent effect on the holding current (Vh = -80 mV) or input resistance and altered neither the kinetic properties, nor the reversal potential of IPSCs. Concomittant to IPSC depression, baclofen enhanced the paired-pulse ratio for two consecutive IPSCs [interstimulus interval (ISI): 50 ms], an effect consistent with a presynaptic locus of action. Both actions of baclofen were abolished by CGP35348 (500 microM), a GABAB receptor antagonist. In testing for involvement of synaptically activated presynaptic GABAB receptors, we only recorded paired-pulse facilitation at most ISIs tested (50-500 ms), suggesting that the classical GABAB autoreceptors may not normally be activated in our conditions. However, enhancement of local GABA concentration by perfusion of a GABA uptake inhibitor (NO-711) revealed an action of endogenous GABA at these presynaptic GABAB receptors. The nonselective K+ channel blocker Ba2+ abolished baclofen's effect and pertussis toxin (PTX) pretreatment (200-500 ng/ml for 18-24 h) was ineffective in blocking the baclofen-induced inhibition, making an involvement of PTX-sensitive G protein unlikely. The present results show that presynaptic GABAB receptors that are coupled to PTX-insensitive G-proteins may be activated by endogenous GABA under conditions of reduced GABA uptake, thus regulating the inhibitory synaptic input to SON.

Animals↗
PubMed1999

Activity-dependent depression of GABAergic IPSCs in cultured hippocampal neurons.

Short-term depression of monosynaptic GABAergic inhibitory postsynaptic currents (IPSCs) evoked between pairs of cultured rat hippocampal neurons was investigated using dual whole cell patch-clamp recordings. Paired stimuli applied to the GABAergic neuron resulted in paired-pulse depression (PPD) of the second IPSC (IPSC2) at interpulse intervals from 25 to 2,000 ms. CGP 55845A, but not CGP 35348, reduced PPD marginally. Brief paired-pulse applications of exogenous GABA indicated that postsynaptic factors made only minimal contribution to PPD of IPSCs. IPSC1 and PPD was reduced on lowering [Ca2+]o and enhanced on increasing [Ca2+]o. The potassium-channel blocker 4-aminopyridine (4-AP), which increases presynaptic Ca2+ influx, enhanced IPSC1 and PPD. Chelation of residual Ca2+ in the GABAergic boutons with EGTA-AM enhanced PPD. Stimulation of the presynaptic neuron at frequencies (f) ranging from 2.5 to 80 Hz resulted in tetanic depression of IPSCs, which declined rapidly and reached a plateau depending on f and [Ca2+]o. CGP 55845A decreased tetanic depression in the first part of the train, but this could be overcome with continued stimulation. We show that GABAergic IPSCs are robustly depressed by paired-pulse stimulation in cultured hippocampal neurons. The depression of IPSCs is mainly independent of presynaptic GABAB receptors and could be caused by depletion of releasable vesicles. Depleted synapses recover with a slow time course, depending on factors that regulate [Ca2+]i in the GABAergic boutons.

4-Aminopyridine↗
PubMed1999

Presynaptic mu and delta opioid receptor modulation of GABAA IPSCs in the rat globus pallidus in vitro.

The role of enkephalin and the opioid receptors in modulating GABA release within the rat globus pallidus (GP) was investigated using whole-cell patch recordings made from visually identified neurons. Two major GP neuronal subtypes were classified on the basis of intrinsic membrane properties, action potential characteristics, the presence of the anomalous inward rectifier (Ih), and anode break depolarizations. The mu opioid receptor agonist [D-Ala2-N-Me-Phe4-Glycol5]-enkephalin (DAMGO) (1 microM) reduced GABAA receptor-mediated IPSCs evoked by stimulation within the striatum. DAMGO also increased paired-pulse facilitation, indicative of presynaptic mu opioid receptor modulation of striatopallidal input. In contrast, the delta opioid agonist D-Pen-[D-Pen2, 5]-enkephalin (DPDPE) (1 microM) was without effect. IPSCs evoked by stimulation within the GP were depressed by application of [methionine 5']-enkephalin (met-enkephalin) (30 microM). Met-enkephalin also reduced the frequency, but not the amplitude, of miniature IPSCs (mIPSCs) and increased paired-pulse facilitation of evoked IPSCs, indicative of a presynaptic action. Both DAMGO and DPDPE reduced evoked IPSCs and the frequency, but not amplitude, of mIPSCs. However, spontaneous action potential-driven IPSCs were reduced in frequency by met-enkephalin and DAMGO, whereas DPDPE was without effect. Overall, these results indicate that presynaptic mu opioid receptors are located on striatopallidal terminals and pallidopallidal terminals of spontaneously firing GP neurons, whereas presynaptic delta opioid receptors are preferentially located on terminals of quiescent GP cells. Enkephalin, acting at both of these receptor subtypes, serves to reduce GABA release in the GP and may therefore act as an adaptive mechanism, maintaining the inhibitory function of the GP in basal ganglia circuitry.

2-Amino-5-phosphonovalerate↗
PubMed2000

Functional correlation of GABA(A) receptor alpha subunits expression with the properties of IPSCs in the developing thalamus.

GABA(A) receptor alpha1 and alpha2 subunits are expressed differentially with ontogenic period in the brain, but their functional roles are not known. We have recorded GABA(A) receptor-mediated IPSCs from laterodorsal (LD) thalamic relay neurons in slices of rat brain at various postnatal ages and found that decay times of evoked IPSCs and spontaneous miniature IPSCs undergo progressive shortening during the first postnatal month. With a similar time course, expression of transcripts and proteins of GABA(A) receptor alpha2 subunit in LD thalamic region declined, being replaced by those of alpha1 subunit. To further address the causal relationship between alpha subunits and IPSC decay time kinetics, we have overexpressed GABA(A) receptor alpha1 subunit together with green fluorescent protein in LD thalamic neurons in organotypic culture using recombinant Sindbis virus vectors. Miniature IPSCs recorded from the LD thalamic neurons overexpressed with alpha1 subunit had significantly faster decay time compared with control expressed with beta-galactosidase. We conclude that the alpha2-to-alpha1 subunit switch underlies the developmental speeding in the decay time of GABAergic IPSCs.

Animals↗
PubMed1995

Delta and mu enkephalins inhibit spontaneous GABA-mediated IPSCs via a cyclic AMP-independent mechanism in the rat hippocampus.

The effects of enkephalins selective for delta and mu opioid receptors on inhibitory postsynaptic currents (IPSCs) mediated by GABA were studied in chloride-loaded CA1 pyramidal neurons in adult rat hippocampal slices. The mu agonist DAMGO (0.1 microM) significantly reduced the amplitudes of evoked monosynaptic IPSCs, recorded following the antagonism of excitatory glutamate receptors, and this effect was reversed by the mu antagonist CTOP (1 microM). The selective delta receptor agonists DPDPE and D-Ala2-deltorphin II (both 0.1-0.5 microM) had no effect on these evoked currents. In contrast, the frequency of tetrodotoxin-resistant spontaneous miniature GABA-mediated currents (m-IPSCs) was significantly reduced by both DPDPE (0.1-0.5 microM) and DAMGO (0.1-0.5 microM), while the amplitudes of these events were unaltered. These effects were reversed by the selective delta antagonist ICI 174,864 (1 microM) and the selective mu antagonist CTOP (1 microM), respectively. To investigate the mechanisms of this mu and delta receptor-mediated modulation of GABA release, and the possible involvement of a cAMP-sensitive K+ conductance, spontaneous action potential-dependent IPSCs (s-IPSCs) were measured following pretreatment with 8-bromo-cAMP (8-Br-cAMP). 8-Br-cAMP (250 microM) had no effect alone on the amplitude or frequency of s-IPSCs, nor did it alter the inhibitory effects of the delta and mu agonists. These results indicate that delta and mu opioid receptor activation inhibits spontaneous GABA release, independently of cAMP, through direct actions at inhibitory nerve terminals, and that delta opioids inhibit spontaneous but not evoked GABA release in the hippocampus.

Animals↗
PubMed1996

Paired pulse facilitation of GABAergic IPSCs in ventral horn neurons in neonatal rat spinal cord.

Whole-cell patch-clamp recording of GABAergic inhibitory postsynaptic currents (IPSCs) were made in ventral horn neurons of neonatal rat lumbar spinal cord in slice. In contrast to the hippocampus where paired pulse depression is reported to be observed for GABAergic IPSCs, double pulse stimulation of GABAergic inputs resulted in enhancement in the amplitude of the second IPSC in the spinal ventral horn. The facilitation ratio was decreased during enhanced synaptic transmission by increasing Ca2+ concentration in the external recording solution. Baclofen and adenosine. which are reported to depress synaptic transmission by presynaptic mechanisms, depressed IPSCs and increased the facilitation ratio. A postsynaptic manipulation such as application of bicuculline or changing the driving force did not affect the facilitation ratio. These results suggest that paired pulse facilitation of GABAergic IPSCs observed in neonatal rat spinal ventral horn appears to be based upon a mechanism similar to that underlying frequency-dependent facilitation of excitatory synaptic transmission, and is sensitive to presynaptic changes in synaptic strength.

Adenosine↗
PubMed2026

Development of a human iPSC and patient phenotyping resource for preclinical investigations of neurodevelopmental disorders.

In this manuscript, we report the development of a comprehensive resource designed to harness the transformative potential of patient-derived induced pluripotent stem cells (iPSCs) to advance the study of neurodevelopmental disorders (NDDs). Using CRISPR-Cas-mediated genome editing, the Human Neuron Core generated a repository comprising 29 isogenic iPSC pairs, two sex-matched parental control iPSC pairs, and one unmatched patient line representing six monogenic NDDs: Tuberous Sclerosis Complex, PTEN Hamartoma Tumor Syndrome, KCNQ2 Developmental and Epileptic Encephalopathy, FOXG1 Syndrome, Phelan-McDermid Syndrome, and SETBP1 Haploinsufficiency Disorder. In parallel, detailed clinical phenotyping data were collected to enable comparison of cellular phenotypes with clinical severity in future studies. This integrated collection of genetically defined iPSC lines and associated clinical data provides a powerful platform for investigating disease mechanisms and advancing iPSC-based drug discovery for NDDs.

Humans↗
PubMed1998

Inhibition of spontaneous inhibitory postsynaptic currents (IPSC) by noradrenaline in rat supraoptic neurons through presynaptic alpha2-adrenoceptors.

It has been shown that noradrenergic activation has great influence on the activities of hypothalamic supraoptic neurons. No direct evidence has been reported on the presynaptic effects of adrenoceptors in the actions of noradrenaline on supraoptic neurons, although postsynaptic mechanisms have been studied extensively. In the present study, we explored presynaptic effects of noradrenaline on the supraoptic neurons by measuring spontaneous inhibitory postsynaptic currents (IPSC) with the whole-cell patch-clamp technique. Noradrenaline reduced the frequency of IPSCs in a dose-dependent (10(-9) to 10(-3) M) and reversible manner. Noradrenaline did not affect the amplitude of IPSCs at concentrations of 10(-9) to 10(-5) M, but reduced the amplitude of IPSCs at high concentrations (10(-4) and 10(-3) M). The inhibitory effects of noradrenaline were mimicked by the alpha2-agonist clonidine (10(-4) M), but not by the alpha1-agonist methoxamine (10(-4) M) nor by the beta-agonist isoproterenol (10(-4) M). Moreover, the inhibitory effects of noradrenaline on IPSCs were blocked by the non-selective alpha antagonist phentolamine (10(-4) M) or the selective alpha2-antagonist yohimbine (10(-4) M), but not by the alpha1-antagonist prazosin (10(-4) M). These results suggest that noradrena-line inhibits release of GABA from the presynaptic GABAergic terminals of the supraoptic neurons by activating presynaptic alpha2-adrenoceptors and such presynaptic mechanisms may play a role in the excitatory control of SON neurons by noradrenergic neurons.

Adrenergic Agents↗