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PubMed2002

GABA and glycine co-release optimizes functional inhibition in rat brainstem motoneurons in vitro.

Whole-cell patch clamp recordings of miniature inhibitory postsynaptic currents (mIPSCs) were obtained in identified abducens motoneurons (aMns) from young rats (P5-P13). Three types of mIPSC were distinguished according to their kinetics and their sensitivity to receptor antagonists: faster decaying events mediated by glycine receptors (glyRs), slower decaying events mediated by GABA(A) receptors (GABA(A)Rs), and mIPSCs displaying two components corresponding to GABA and glycine co-release. Dual component events accounted for approximately 30 % of mIPSCs, independently of the rat's age and were also identified during evoked transmitter release. In contrast, the kinetics of glyR- and GABA(A)R-mediated mIPSCs became faster during development. Monosynaptic inhibitory postsynaptic potentials (IPSPs) were able to fully inhibit motoneuron discharge elicited by current pulses. When the GABA(A)R-mediated component or the glyR-mediated component of the IPSP was blocked, the inhibition of motoneuron firing was reduced. The 20-80 % rise time and duration of GABA(A)R-mediated IPSPs were significantly longer than those mediated by glyRs. The time window of inhibition for each component was determined using single postsynaptic action potentials elicited with various delays from the onset of the IPSP. GlyR-mediated IPSPs induced fast transient inhibition whereas GABA(A)R-mediated IPSPs induced slow sustained suppression of firing. Using a modelling approach, we found that the two components summated non-linearly. We conclude that in developing aMns, co-release of GABA and glycine determines the strength and timing of inhibition through non-linear interactions between the two components, thus optimizing inhibition of motoneuron function.

Animals↗

PubMed2003

Cell signal control of the G protein-gated potassium channel and its subcellular localization.

G protein-gated inward rectifier K(+) (K(G)) channels are directly activated by the betagamma subunits released from pertussis toxin-sensitive G proteins, and contribute to neurotransmitter-induced deceleration of heart beat, formation of slow inhibitory postsynaptic potentials in neurones and inhibition of hormone release in endocrine cells. The physiological roles of K(G) channels are critically determined by mechanisms which regulate their activity and their subcellular localization. K(G) channels are tetramers of inward rectifier K(+) (Kir) channel subunits, Kir3.x. The combination of Kir3.x subunits in each K(G) channel varies among tissues and cell types. Each subunit of the channel possesses one Gbetagamma binding site. The binding of Gbetagamma increases the number of functional K(G) channels via a mechanism that can be described by the Monod-Wyman-Changeux allosteric model. During voltage pulses K(G) channel current alters time dependently. The K(G) current exhibits inward rectification due to blockade of outward-going current by intracellular Mg(2+) and polyamines. Upon repolarization, this blockade is relieved practically instantaneously and then the current slowly increases further. This slow current alteration is called 'relaxation'. Relaxation is caused by the voltage-dependent behaviour of regulators of G protein signalling (RGS proteins), which accelerate intrinsic GTP hydrolysis mediated by the Galpha subunit. Thus, the relaxation behaviour of K(G) channels reflects the time course with which the G protein cycle is altered by RGS protein activity at each membrane potential. Subcellular localization of K(G) channels is controlled by several distinct mechanisms, some of which have been recently clarified. The neuronal K(G) channel, which contains Kir3.2c, is localized in the postsynaptic density (PSD) of various neurones including dopaminergic neurones in substantia nigra. Its localization at PSD may be controlled by PDZ domain-containing anchoring proteins. The K(G) channel in thyrotrophs is localized exclusively on secretary vesicles, which upon stimulation are rapidly inserted into the plasma membrane and causes hyperpolarization of the cell. This mechanism indicates a novel negative feedback regulation of exocytosis. In conclusion, K(G) channels are under the control of a variety of signalling molecules which regulate channel activity, subcellular localization and thus their physiological roles in myocytes, neurones and endocrine cells.

Animals↗

PubMed2003

Activation and integration of bilateral GABA-mediated synaptic inputs in neonatal rat sympathetic preganglionic neurones in vitro.

The role of GABA receptors in synaptic transmission to neonatal rat sympathetic preganglionic neurones (SPNs) was investigated utilizing whole-cell patch clamp recording techniques in longitudinal and transverse spinal cord slice preparations. In the presence of glutamate receptor antagonists (NBQX, 5 microm and D-APV, 10 microm), electrical stimulation of the ipsilateral or contralateral lateral funiculi (iLF and cLF, respectively) revealed monosynaptic inhibitory postsynaptic potentials (IPSPs) in 75% and 65% of SPNs, respectively. IPSPs were sensitive to bicuculline (10 microM) in all neurones tested and reversed polarity around -55 mV, the latter indicating mediation via chloride conductances. In three neurones IPSPs evoked by stimulation of the iLF (n = 1) or cLF (n = 2) were partly sensitive to strychnine (2 microM). The expression of postsynaptic GABA(A) and GABA(B) receptors were confirmed by the sensitivity of SPNs to agonists, GABA (2 mm), muscimol (10-100 microM) or baclofen (10-100 microM), in the presence of TTX, each of which produced membrane hyperpolarization in all SPNs tested. Muscimol-induced responses were sensitive to bicuculline (1-10 microM) and SR95531 (10 microM) and baclofen-induced responses were sensitive to 2-hydroxy-saclofen (100-200 microM) and CGP55845 (200 nM). The GABA(C) receptor agonist CACA (200 microM) was without significant effect on SPNs. These results suggest that SPNs possess postsynaptic GABA(A) and GABA(B) receptors and that subsets of SPNs receive bilateral GABAergic inputs which activate GABA(A) receptors, coupled to a chloride conductance. At resting or holding potentials close to threshold either single or bursts (10-100 Hz) of IPSPs gave rise to a rebound excitation and action potential firing at the termination of the burst. This effect was mimicked by injection of small (10-20 pA) rectangular-wave current pulses, which revealed a time-dependent, Cs(+)-sensitive inward rectification and rebound excitation at the termination of the response to current injection. Synaptic activation of a rebound excitation mediated by a time-dependent inward rectification expressed intrinsically by SPNs may provide a novel mechanism enabling SPNs to be entrained to rhythms driven from the brainstem or higher centres.

Adrenergic Fibers↗

PubMed2000

Regulation of central synaptic transmission by 5-HT(1B) auto- and heteroreceptors.

Although 5-HT(1B) receptors are believed to be expressed on nerve terminals, their precise mode of action is not fully understood because of the lack of selective antagonists. The 5-HT(1B) receptor knockout mouse was used in the present investigation to assess the function of 5-HT(1B) receptors in the modulation of synaptic transmission in three areas of the central nervous system: the dorsal raphe, the ventral midbrain, and the nucleus accumbens. N-(3-Trifluoromethylphenyl)piperazine, a 5-HT(1B) receptor agonist, potently inhibited 5-HT(1A) receptor-mediated slow inhibitory postsynaptic potentials (IPSPs) in the dorsal raphe of wild-type but not knockout mice. Both synaptically released 5-HT and exogenous 5-HT caused a presynaptic inhibition that outlasted the postsynaptic hyperpolarization only in wild-type mice. In the ventral midbrain, 5-HT(1B) receptor-dependent inhibition of gamma-aminobutyric acid(B) IPSPs in dopamine neurons was present in wild-type animals and absent in knockout animals. Similar results were obtained in the nucleus accumbens measuring glutamate-mediated excitatory postsynaptic currents in medium spiny neurons. Finally, cocaine, which blocks 5-HT uptake, inhibited IPSPs in the dorsal raphe and the ventral midbrain of wild-type but not knockout mice, whereas cocaine produced comparable inhibition of excitatory postsynaptic currents in the nucleus accumbens of both types of animals. These results indicate that 5-HT(1B) receptors function as autoreceptors and heteroreceptors to exert presynaptic inhibition of transmitter release in the central nervous system. Furthermore, this study underscores the role played by presynaptic 5-HT(1B) receptors in mediating the effects of cocaine on synaptic transmission.

Animals↗

PubMed1991

Excitatory synaptic responses mediated by GABAA receptors in the hippocampus.

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the cortex. Activation of postsynaptic GABAA receptors hyperpolarizes cells and inhibits neuronal activity. Synaptic responses mediated by GABAA receptors also strongly excited hippocampal neurons. This excitatory response was recorded in morphologically identified interneurons in the presence of 4-aminopyridine or after elevation of extracellular potassium concentrations. The synaptic excitation sustained by GABAA receptors synchronized the activity of inhibitory interneurons. This synchronized discharge of interneurons in turn elicited large-amplitude inhibitory postsynaptic potentials in pyramidal and granule cells. Excitatory synaptic responses mediated by GABAA receptors may thus provide a mechanism for the recruitment of GABAergic interneurons through their recurrent connections.

4-Aminopyridine↗

PubMed1977

Cyclic nucleotides injected intracellularly into rat superior cervical ganglion cells.

Intracellular iontophoresis of either adenosine 3',5'-monophosphate or guanosine 3',5'-monophosphate produces a membrane depolarization and an increased membrane conductance in sympathetic ganglion cells of the rat superior cervical ganglion. Since adenosine 3',5'-monophosphate did not cause a membrane hyperpolarization, it is difficult to assign it a second messenger role in the mediation of the slow inhibitory postsynaptic potential. However, these results do not rule out the possibility that the cyclic nucleotides, at the intracellular concentrations attained in these experiments, participate in cellular processes that contribute to conductance changes which result in depolarization of the ganglion cell membrane.

Action Potentials↗

PubMed1997

Functional dynamics of GABAergic inhibition in the thalamus.

The inhibitory gamma-aminobutyric acid-containing (GABAergic) neurons of the thalamic reticular and perigeniculate nuclei are involved in the generation of normal and abnormal synchronized activity in thalamocortical networks. An important factor controlling the generation of activity in this system is the amplitude and duration of inhibitory postsynaptic potentials (IPSPs) in thalamocortical cells, which depend on the pattern of activity generated in thalamic reticular and perigeniculate cells. Activation of single ferret perigeniculate neurons generated three distinct patterns of GABAergic IPSPs in thalamocortical neurons of the dorsal lateral geniculate nucleus: Low-frequency tonic discharge resulted in small-amplitude IPSPs mediated by GABAA receptors, burst firing resulted in large-amplitude GABAA IPSPs, and prolonged burst firing activated IPSPs mediated by GABAA and GABAB receptors. These functional properties of GABAergic inhibition can reconfigure the operations of thalamocortical networks into patterns of activity associated with waking, slow-wave sleep, and generalized seizures.

Action Potentials↗

PubMed1982

Substance P: a putative sensory transmitter in mammalian autonomic ganglia.

Repetitive presynaptic stimulation elicited slow membrane depolarization in neurons of inferior mesenteric ganglia from guinea pigs. This response was not blocked by cholinergic antagonists but was specifically and reversibly inhibited by a substance P analog, (D-Pro2, D-Phe7, D-Trp9)-substance P, which also depressed the depolarization induced by exogenously applied substance P. The atropine-sensitive slow excitatory and slow inhibitory postsynaptic potentials evoked in neurons of rabbit superior cervical ganglia were not affected by the substance P analog. These and previous results provide strong support for the hypothesis that substance P or a closely related peptide is the transmitter mediating the slow depolarization. The latter may represent a sensory input from the gastrointestinal tract to neurons of the prevertebral ganglia.

Action Potentials↗

PubMed1981

Fluctuating responses at a central synapse: n of binomial fit predicts number of stained presynaptic boutons.

Binomial predictions provided a better description than the Poisson law of fluctuating unitary inhibitory postsynaptic potentials evoked in the goldfish Mauthner cell by impulses in presynaptic interneurons. The number of terminal boutons established on this target cell by each horseradish peroxidase-filled interneuron corresponded to the value of the binomial parameter n.

Animals↗

PubMed1984

Decreased neuronal inhibition in vitro after long-term administration of ethanol.

The pathophysiology of brain dysfunction was studied with an animal model of chronic alcoholism. Rats were fed a liquid diet with or without ethanol for 20 weeks and then the diet without ethanol for three more weeks. Hippocampal slices were prepared and intracellular recordings were obtained from dentate granule and CA1 cells. Significant depression of orthodromically elicited inhibitory postsynaptic potentials and postspike afterhyperpolarizations was observed in neurons from ethanol-exposed animals. No differences were observed in other active or passive membrane characteristics. These results suggest that a loss of neuronal inhibition could contribute to brain dysfunction in chronic alcoholism.

Action Potentials↗

PubMed1984

Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats.

The possibility that calcium is elevated in brain neurons during aging was examined by quantifying afterhyperpolarizations induced by spike bursts in CAl neurons of hippocampal slices from young and aged rats. The afterhyperpolarizations result from Ca2+-dependent K+ conductance increases and are blocked in medium low in Ca2+ and prolonged in medium high in Ca2+. The afterhyperpolarization and associated conductance increases were considerably prolonged in cells from aged rats, although inhibitory postsynaptic potentials did not differ with age. Since elevated intracellular Ca2+ can exert deleterious effects on neurons, the data suggest that altered Ca2+ homeostasis may play a significant role in normal brain aging.

Action Potentials↗

PubMed1993

Dormancy of inhibitory interneurons in a model of temporal lobe epilepsy.

In humans temporal lobe epilepsy (TLE) is characterized by recurrent seizures, neuronal hyperexcitability, and selective loss of certain neuronal populations in the hippocampus. Animal models of the condition indicate that a diminution of inhibition mediated by gamma-aminobutyric acid (GABA) accounts for the altered function, and it has been hypothesized that the diminution arises because GABAergic basket interneurons are "dormant" as a result of their being disconnected from excitatory inputs. In hippocampal slices, inhibitory postsynaptic potentials (IPSPs) were elicited in CA1 pyramidal cells by activation of basket cells; responses from an animal model of TLE were compared to those from control tissue. IPSPs evoked indirectly by activation of terminals that then excited basket cells were reduced in the epileptic tissue, whereas IPSPs evoked by direct activation of basket cells, when excitatory neurotransmission was blocked, were not different from controls. These results provide support for the "dormant basket cell" hypothesis and have implications for the pathophysiology and treatment of human TLE.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2004

Rapid desensitization of G protein-gated inwardly rectifying K(+) currents is determined by G protein cycle.

Activation of G protein-gated inwardly rectifying K(+) (GIRK) channels, found in the brain, heart, and endocrine tissue, leads to membrane hyperpolarization that generates neuronal inhibitory postsynaptic potentials, slows the heart rate, and inhibits hormone release. During stimulation of G(i/o)-coupled receptors and subsequent channel activation, it has been observed that the current desensitizes. In this study we examined mechanisms underlying fast desensitization of cloned heteromeric neuronal Kir3.1+3.2A and atrial Kir3.1+3.4 channels and also homomeric Kir3.0 currents in response to stimulation of several G(i/o) G protein-coupled receptors (GPCRs) expressed in HEK-293 cells (adenosine A(1), adrenergic alpha(2A), dopamine D(2S), M(4) muscarinic, and GABA(B1b/2) receptors). We found that all agonist-induced currents displayed a similar degree of desensitization except the adenosine A(1) receptor, which exhibits an additional desensitizing component. Using the nonhydrolyzable GTP analog guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS), we found that this is due to a receptor-dependent, G protein-independent process. Using Ca(2+) imaging we showed that desensitization is unlikely to be accounted for solely by phospholipase C activation and phosphatidylinositol 4,5-bisphosphate (PIP(2)) hydrolysis. We examined the contribution of the G protein cycle and found the following. First, agonist concentration is strongly correlated with degree of desensitization. Second, competitive inhibition of GDP/GTP exchange by using nonhydrolyzable guanosine 5'-O-(2-thiodiphosphate) (GDPbetaS) has two effects, a slowing of channel activation and an attenuation of the fast desensitization phenomenon. Finally, using specific Galpha subunits we showed that ternary complexes with fast activation rates display more prominent desensitization than those with slower activation kinetics. Together our data suggest that fast desensitization of GIRK currents is accounted for by the fundamental properties of the G protein cycle.

Cell Line↗

PubMed2001

Glutamate and GABA mediate suprachiasmatic nucleus inputs to spinal-projecting paraventricular neurons.

We used patch-clamp recordings in slice preparations from Sprague-Dawley rats to evaluate responses of 20 spinal-projecting neurons in the dorsal paraventricular nucleus (PVN) to electrical stimulation in suprachiasmatic nucleus (SCN). Neurons containing a retrograde label transported from the thoracic (T(1)-T(4)) intermediolateral column displayed three intrinsic properties that collectively allowed distinction from neighboring parvocellular or magnocellular cells: a low-input resistance, a hyperpolarization-activated time-dependent inward rectification, and a low-threshold calcium conductance. Twelve of fifteen cells tested responded to electrical stimulation in SCN. All of 10 cells tested in media containing 2,3,-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium (5 microM) and D(-)-2-amino-5-phosphonopentanoic acid (20 microM) responded with constant latency (11.4 +/- 0.7 ms) inhibitory postsynaptic potentials, able to follow 20- to 50-Hz stimulation and blockable with bicuculline (20 microM). By contrast, all eight cells tested in the presence of bicuculline demonstrated constant latency (9.8 +/- 0.6 ms) excitatory postsynaptic potentials that followed at 20-50 Hz and featured both non-N-methyl-D-aspartate (NMDA) and NMDA receptor-mediated components. We conclude that both GABAergic and glutamatergic neurons in SCN project directly to spinal-projecting neurons in the dorsal PVN.

2-Amino-5-phosphonovalerate↗

PubMed2003

Mechanism for activation of locomotor centers in the spinal cord by stimulation of the mesencephalic locomotor region.

The synaptic pathways of mesencephalic locomotor region (MLR)-evoked excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) recorded from lumbar motoneurons of unanesthetized decerebrate cats during fictive locomotion were analyzed prior to, during, and after cold block of the medial reticular formation (MedRF) or the low thoracic ventral funiculus (VF). As others have shown, electrical stimulation of the MLR typically evoked short-latency excitatory or mixed excitatory/inhibitory PSPs in flexor and extensor motoneurons. The bulbospinal conduction velocities averaged approximately 88 m/s (range: 62-145 m/s) and segmental latencies for EPSPs ranged from 1.2 to 10.9 ms. The histogram of segmental latencies showed three peaks, suggesting di-, tri-, and polysynaptic linkages. Segmental latencies for IPSPs suggested trisynaptic or polysynaptic transmission. Most EPSPs (69/77) were significantly larger during the depolarized phase of the intracellular locomotor drive potential (LDP), and most IPSPs (35/46) were larger during the corresponding hyperpolarized phase. Bilateral cooling of the MedRF reversibly abolished locomotion of both hindlimbs as measured from the electroneurogram (ENG) activity of muscle nerves and simultaneously abolished or diminished the motoneuron PSPs and LDPs. Unilateral cooling of the VF blocked locomotion ipsilaterally and diminished it contralaterally with concomitant loss or decrease the motoneuron PSPs and LDPs. Relative to the side of motoneuron recording, cooling of the ipsilateral VF sometimes uncovered longer-latency EPSPs, whereas cooling of the contralateral VF abolished longer-latency EPSPs. It is concluded that MLR stimulation activates a pathway that relays in the MedRF and descends bilaterally in the VF to contact spinal interneurons that project to motoneurons. Local segmental pathways that activate or inhibit motoneurons during MLR-evoked fictive locomotion appear to be both ipsilateral and contralateral.

Animals↗

PubMed2005

Regulation of IPSP theta rhythm by muscarinic receptors and endocannabinoids in hippocampus.

Theta rhythms are behaviorally relevant electrical oscillations in the mammalian brain, particularly the hippocampus. In many cases, theta oscillations are shaped by inhibitory postsynaptic potentials (IPSPs) that are driven by glutamatergic and/or cholinergic inputs. Here we show that hippocampal theta rhythm IPSPs induced in the CA1 region by muscarinic acetylcholine receptors independent of all glutamate receptors can be briefly interrupted by action potential-induced, retrograde endocannabinoid release. Theta IPSPs can be recorded in CA1 pyramidal cell somata surgically isolated from CA3, subiculum, and even from their own apical dendrites. These results suggest that perisomatic-targeting interneurons whose output is subject to inhibition by endocannabinoids are the likely source of theta IPSPs. Interneurons having these properties include the cholecystokinin-containing cells. Simultaneous recordings from pyramidal cell pairs reveal synchronous theta-frequency IPSPs in neighboring pyramidal cells, suggesting that these IPSPs may help entrain or modulate small groups of pyramidal cells.

Action Potentials↗

PubMed2002

Auditory thalamocortical synaptic transmission in vitro.

To facilitate an understanding of auditory thalamocortical mechanisms, we have developed a mouse brain-slice preparation with a functional connection between the ventral division of the medial geniculate (MGv) and the primary auditory cortex (ACx). Here we present the basic characteristics of the slice in terms of physiology (intracellular and extracellular recordings, including current source density analysis), pharmacology (including glutamate receptor involvement), and anatomy (gross anatomy, Nissl, parvalbumin immunocytochemistry, and tract tracing with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate). Thalamocortical transmission in this preparation (the "primary" slice) involves both alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid/kainate and N-methyl-D-aspartate-type glutamate receptors that appear to mediate monosynaptic inputs to layers 3-4 of ACx. MGv stimulation also initiates disynaptic inhibitory postsynaptic potentials and longer-duration intracortical, polysynaptic activity. Important differences between responses elicited by MGv versus conventional columnar ("on-beam") stimulation emphasize the necessity of thalamic activation to infer thalamocortical mechanisms. We also introduce a second slice preparation, the "shell" slice, obtained from the brain region immediately ventral to the primary slice, that may contain a nonprimary thalamocortical pathway to temporal cortex. In the shell slice, stimulation of the thalamus or the region immediately ventral to it appears to produce fast activation of synapses in cortical layer 1 followed by robust intracortical polysynaptic activity. The layer 1 responses may result from orthodromic activation of nonprimary thalamocortical pathways; however, a plausible alternative could involve antidromic activation of corticotectal neurons and their layer 1 collaterals. The primary and shell slices will provide useful tools to investigate mechanisms of information processing in the ACx.

Action Potentials↗

PubMed2003

Independent neuronal oscillators of the rat globus pallidus.

In vivo, neurons of the globus pallidus (GP) and subthalamic nucleus (STN) resonate independently around 70 Hz. However, on the loss of dopamine as in Parkinson's disease, there is a switch to a lower frequency of firing with increased bursting and synchronization of activity. In vitro, type A neurons of the GP, identified by the presence of I(h) and rebound depolarizations, fire at frequencies (<or=80 Hz) in response to glutamate pressure ejection, designed to mimic STN input. The profile of this frequency response was unaltered by bath application of the GABA(A) antagonist bicuculline (10 microM), indicating the lack of involvement of a local GABA neuronal network, while cross-correlations of neuronal pairs revealed uncorrelated activity or phase-locked activity with a variable phase delay, consistent with each GP neuron acting as an independent oscillator. This autonomy of firing appears to arise due to the presence of intrinsic voltage- and sodium-dependent subthreshold membrane oscillations. GABA(A) inhibitory postsynaptic potentials are able to disrupt this tonic activity while promoting a rebound depolarization and action potential firing. This rebound is able to reset the phase of the intrinsic oscillation and provides a mechanism for promoting coherent firing activity in ensembles of GP neurons that may ultimately lead to abnormal and pathological disorders of movement.

Action Potentials↗