GABAA-receptor modification in taurine transporter knockout mice causes striatal disinhibition.

The Striatum is involved in the regulation of movements and motor skills. We have shown previously, that the osmolyte and neuromodulator taurine plays a role in striatal plasticity. We demonstrate now that hereditary taurine deficiency in taurine-transporter knock-out (TAUT KO) mice results in disinhibition of striatal network activity, which can be corrected by taurine supplementation. Modification of GABAA but not glycine receptors (taurine is a ligand for both receptor types) underlies this disinhibition. Whole-cell recordings from acutely isolated as well as cultured striatal neurons revealed a decreased agonist sensitivity of the GABAA receptor in TAUT KO neurons in the absence of changes in the maximal GABA-evoked current amplitude. The striatal GABA level in TAUT KO mice was unchanged. The amplitude enhancement of spontaneous IPSCs by zolpidem was stronger in TAUT KO than in wild-type (WT) animals. Tonic inhibition was absent in striatal neurons under control conditions but was detected after incubation with the GABA-transaminase inhibitor vigabatrin: bicuculline induced a larger shift of baseline current in WT as compared to TAUT KO neurons. Lack of taurine leads to reduced sensitivity of synaptic and extrasynaptic GABAA receptors and consequently to disinhibition. These findings help in understanding neuropathologies accompanied by the loss of endogenous taurine, for instance in hepatic encephalopathy.

Long-term depression of cortico-striatal synaptic transmission by DHPG depends on endocannabinoid release and nitric oxide synthesis.

In models of early stage Parkinson's disease (PD), motor deficits are accompanied by excessive activation of striatal glutamate receptors. Metabotropic glutamate group I receptors (mGluR I) play an important but not well-understood role in PD progression. In mouse brain slices, bath application of the mGluR I agonist (RS)-DHPG (3,5-dihydroxyphenylglycine, 100 microm for 20 min) caused a long-term depression of corticostriatal transmission (LTD(DHPG)), which was reversed by three mGluR I antagonists: LY 367385, CPCCOEt and MPEP. LTD(DHPG) required nitric oxide (NO) synthesis as it was blocked by the broad-spectrum NO synthase (NOS) inhibitor Nomega-nitro-l-arginine (NL-Arg) and impaired under blockade of neuronal NOS and in endothelial NOS-deficient mice. Release of endocannabinoids (eCB) was critically involved in this form of striatal plasticity givem that the CB1 receptor antagonist AM251 prevented LTD(DHPG), while the CB1 agonist ACEA elicited LTD. The NO synthesis necessary for LTD(DHPG) induction occurred downstream of CB1 activation as ACEA-evoked LTD was also abolished by NL-Arg. These findings are relevant for the pathophysiology of PD, as they link the overactivation of group I mGluRs and striatal NO production.

Long-lasting enhancement of corticostriatal transmission by taurine: role of dopamine and acetylcholine.

1. Taurine applied to mouse brain slices evokes a long-lasting enhancement (LLE) of corticostriatal synaptic transmission, LLE(TAU). 2. The occurrence of LLE(TAU) was significantly decreased in the presence of the specific antagonists at either D1 (SCH23390) or D2 (raclopride) dopamine (DA) receptors. 3. LLE(TAU) was prevented by scopolamine, a muscarinic antagonist, and significantly suppressed by the nicotinic antagonist mecamylamine. 4. Thus, dopaminergic and cholinergic mechanisms, in concert with the taurine transporter and glycine receptors, contribute critically to the induction of corticostriatal LLE(TAU).

Pyroglutamyl-asparagine amide normalizes long-term potentiation in rat hippocampal slices.

Preapplication of peptide piracetam analogue pyroglutamyl-asparagine amide to rat hippocampal slices facilitates long-term potentiation of focal responses in the CA1 field after weak tetanization of the synaptic input (30 pulses, 100 Hz). This treatment normalized the development of long-term potentiation after standard tetanization (100 pulses, 100 Hz) impaired by ethanol.

Effect of pyroglutamylasparagine amide on plastic characteristics of synaptic transmission in the hippocampus.

Preincubation of rat hippocampal slices with 0.05-0.5 microM pyroglutamylasparagine amide improved characteristics of long-term potentiation of focal responses in the synaptic system of Schaffer collaterals-CA1 field pyramids facilitating LTP development and increasing its amplitude and duration. Presumably, the positive modulation of plastic characteristics of synaptic transmission in the hippocampusis is responsible for facilitation of learning and memory induced by pyroglutamylasparagine.

Taurine-induced long-lasting enhancement of synaptic transmission in mice: role of transporters.

Taurine, a major osmolyte in the brain evokes a long-lasting enhancement (LLETAU) of synaptic transmission in hippocampal and cortico-striatal slices. Hippocampal LLETAU was abolished by the GABA uptake blocker nipecotic acid (NPA) but not by the taurine-uptake inhibitor guanidinoethyl sulphonate (GES). Striatal LLETAU was sensitive to GES but not to NPA. Semiquantitative PCR analysis and immunohistochemistry revealed that taurine transporter expression is significantly higher in the striatum than in the hippocampus. Taurine transporter-deficient mice displayed very low taurine levels in both structures and a low ability to develop LLETAU in the striatum, but not in the hippocampus. The different mechanisms of taurine-induced synaptic plasticity may reflect the different vulnerabilities of these brain regions under pathological conditions that are accompanied by osmotic changes such as hepatic encephalopathy.

Comenic acid prevents post-stress enhancement of long-term potentiation in rat hippocampus.

In experiments on hippocampal slices from young rats subjected to immobilization-cold stress we observed a pronounced increase in the amplitude of long-term potentiation of focal responses in CA1 area. Daily injections of comenic acid during stress exposure normalized parameters of long-term potentiation in the hippocampus.

Long-lasting enhancement of corticostriatal neurotransmission by taurine.

Taurine occurs at high concentrations in the forebrain and its distribution varies with (patho)physiological conditions; however, its role in neural function is poorly understood. We have now characterized its effects on corticostriatal synaptic transmission. Bath application of taurine (10 mm) to slices obtained from mice and rats exerted a biphasic action on corticostriatal field potentials. The fast and reversible inhibition by taurine was accompanied by a depolarization and conductance increase in medium spiny neurons and was sensitive to gamma-aminobutyric acid (GABA)A and glycine receptor (GlyR) antagonists. A long-lasting enhancement (LLETAU) of field potentials was recorded after taurine withdrawal. The LLETAU was not prevented by N-methyl-d-aspartate (NMDA)- or by GABAA receptor-antagonists, but was sensitive to the GlyR-antagonist strychnine and blocked by the competitive taurine uptake inhibitor guanidinoethylsulphonate (GES, 1 mm). GES at 10 mm evoked an enhancement of field potentials similar to LLETAU. LLETAU depended on protein kinase C activation as it was blocked by chelerythrine, but was unaffected by trifluoperazine, and thus independent of calmodulin. LLETAU was significantly smaller in juvenile than in mature rodents. Activation of GlyRs and the specific taurine transporter by taurine evoke a long-lasting enhancement of corticostriatal transmission.

Arginine vasopressin fragment AVP(4-9)facilitates induction of long-term potentiation in the hippocampus.

Long-term potentiation of CA1 field potentials was induced by weak tetanic orthodromic stimulation of the Schaffer collateral/commissural fibers in isolated hippocampal slices perfused with a medium containing arginine vasopressin fragment AVP(4-9)in micromolar concentrations. It is hypothesized that AVP(4-9)affects induction of long-term potentiation at the intracellular level.

[Synaptic plasticity in learning and memory]. / Sinapticheskaia plastichnost' v aspekte obucheniia i pamiati.

Pavlovian conditioning has been considered as one of the principal experimental approaches to understanding such complex brain functions as learning and memory. Use-dependent alterations in synaptic efficacy are believed to form the basis for these functions. The algorithm of synapse modification proposed by D. Hebb as early as 1949 is the coincident activation of pre- and postsynaptic neurons. The present review considers the evolution of experimental protocols which were used to reveal the manifestations of Hebb-type plasticity in the synaptic inputs to neocortical and hippocampal neurons. Special attention is focused on long-term modifications of synaptic efficacy in the hippocampus as a possible neuronal mechanism of learning and the role of disinhibition in their development. The effects of various neuromodulators on hippocampal long-term potentiation are considered. It is suggested that along with their involvement in disinhibition processes these substances may control the Hebb-type plasticity through intracellular second messenger systems.

Hebbian synapses in cortical and hippocampal pathways.

Use-dependent alterations in synaptic efficacy are believed to form the basis for such complex brain functions as learning and memory and significantly contribute to the development of neuronal networks. The algorithm of synapse modification proposed by Hebb as early as 1949 is the coincident activation of pre- and postsynaptic neurons. The present review considers the evolution of experimental protocols in which postsynaptic cell depolarization through the recording microelectrode was used to reveal the manifestation of Hebb-type plasticity in the synaptic inputs of the neocortex and hippocampus. Special attention is focused on the inhibitory control of the Hebb-type plasticity. Disinhibition within the local neuronal circuits is considered to be an important factor in Hebbian plasticity, contributing to such phenomena as priming, primed burst potentiation, hippocampal theta-rhythm and cortical arousal. The role of various transmitters (acetylcholine, norepinephrine, gamma-amino-butyric acid) in disinhibition is discussed with a special emphasis on the brain noradrenergic system. Possible mechanisms of Hebbian synapse modification and their modulation by memory enhancing substances are considered. It is suggested that along with their involvement in disinhibition processes these substances may control Hebb-type plasticity through intracellular second messenger systems.

Long-lasting enhancement of synaptic excitability of CA1/subiculum neurons of the rat ventral hippocampus by vasopressin and vasopressin(4-8).

Vasopressin (VP) is axonally distributed in many brain structures, including the ventral hippocampus. Picogram quantities of VP injected into the hippocampus improve the passive avoidance response of rats, presumably by enhancing memory processes. Vasopressin is metabolized by the brain tissue into shorter peptides, such as [pGlu4,Cyt6]VP(4-9) and [pGlu4,Cyt6]VP(4-8), which preserve the behavioral activity but lose the peripheral activities of the parent hormone. Using brain slices, we investigated whether VP or VP(4-8) affects excitatory postsynaptic potentials (EPSPs) and/or membrane responses to depolarization in neurons of the CA1/subiculum of the ventral hippocampus. The EPSPs were evoked by stimulating the striatum radiatum of the CA1 field; the membrane responses were elicited by current injections. Exposure of slices for 15 min to 0.1 nM solution of these peptides resulted in an increase in the amplitude and slope of the EPSPs in 21 neurons (67%) tested. No consistent change in either the resting membrane potential or the input resistance of the neurons was observed. The peptide-induced increase in EPSPs reached a maximum 30-45 min after peptide application. In 14 of these neurons (66%), the peptide-induced increase in EPSPs remained throughout the entire 60-120 min washout period. In the remaining 7 neurons (33%), the initial increase in EPSPs amplitude was followed by a gradual decline to the pre-administration level. The increase in EPSP amplitude was often, but not always, associated with a decrease in the threshold and increase in the number of action potentials in response to depolarizing current injection. Suppression of GABAA receptor-mediated inhibition and N-methyl-D-aspartate (NMDA) receptor-mediated excitation did not prevent the effects of VP and VP(4-8) on the EPSP amplitude or the threshold for action potentials. The results demonstrate that 0.1 nM concentrations of these neuropeptides can elicit a long-lasting enhancement of the excitability of CA1/subiculum neurons of the ventral hippocampus to excitatory, glutamatergic synaptic input. This novel action of VP and its metabolite in the ventral hippocampus may be the physiological action, mediating the memory-enhancing effect of these peptides.

Nootropic compound L-pyroglutamyl-D-alanine-amide restores hippocampal long-term potentiation impaired by exposure to ethanol in rats.

The characteristics of long-term potentiation (LTP) in the hippocampus of rats prenatally exposed to ethanol and treated postnatally with nootropic compounds L-pyroglutamyl-D-alanine-amide (L-pGlu-D-AlaNH2, PGA) or piracetam were studied using in vitro slice preparations. LTP was induced in the CA1 region by the orthodromic stimulation of the stratum radiatum with one train of 100 pulses (100 Hz, 1 s). The probability of LTP development in the hippocampus of young rats was significantly reduced by prenatal exposure to alcohol. This plasticity deficit was completely reversed by daily injections of PGA, 1 mg/kg for 12 days (8-19 days of postnatal development) but not of piracetam, 100 mg/kg. PGA (0.5 microM) also prevented the inhibition of LTP development in hippocampal slices perfused with ethanol, 20 or 50 mM. The data indicate that PGA effectively restores synaptic plasticity after both prenatal and acute exposure to ethanol and suggest that impaired LTP may be a useful model for studying the mechanisms of action of nootropic compounds.

[Preservation of plastic properties of synaptic transmission in long-lasting hippocampal slices under the effects of a peptide analog of piracetam, L-pGlu-D-Ala-NH2]. / Sokhranenie plasticheskikh svoistv sinapticheskoi peredachi v dolgozhivushchikh srezakh gippokampa pod deistviem peptidnogo analoga piratsetama L-pGlu-D-Ala-NH2.

The tetanic stimulation of the Schaffer collaterals (SC) in rat hippocamp slices after 6 hrs in vitro conditions did not produce long-term potentiation (LTP) of the field response amplitude in the CA1 pyramidal cell layer. In contrast, LTP after the late tetanization was well preserved in the slices that were perfused for 20 minutes with 0.5 mkM L-pGlu-D-Ala-NH2 (PGAA) after 4-4.5 hrs in vitro. There were no significant reactivity changes during the perfusion of the slices with this drug concentration. Two other drugs with nootropic activity, piracetam (100 mkM) and gamma-hydroxybutyrate (100 mkM, Na-salt) did not prevent the disappearance of LTP in the late period in vitro, while enhanced the reactivity during perfusion period. The maintenance of the plastic properties of the SC-CA1 synaptic transmission under the influence of PGAA is thought to be the result of some specific interaction of the drug with LTP induction mechanisms. LTP damaged in the late period in vitro might be a new model of memory disturbances and this model can turn out to be useful for the comparative estimation of the effectiveness of the drugs with proposed nootropic activity and for the analysis of the possible mechanisms of their action.

[Effects of polymethylene derivatives of 4-aminopyridine on functional properties of hippocampal neurons]. / Vliianie polimetilenovykh proizvodnykh 4-aminopiridina na funktsional'nye svoistva neironov gippokampa.

The effects of amiridin (9-amino-2,3,5,6,7,8-hexahydro-IH-cyclopenta(b) quinoline) and tacrine (1,2,3,4-tetrahydro-9-aminoacridine) on Schaffer collaterals--CAI field potentials were compared in rat hippocampal slice preparations. Similar dose-dependent increase in pop-spike amplitude was observed during slice perfusion with low concentrations of amiridin (5-50 microM) or tacrine (0.5-10 microM). This facilitation was not always fully reversible. The effect was accompanied by slight decrease in pop-EPSP amplitude suggesting membrane depolarization as a possible mechanism of pop-spike facilitation. Further increase in drug concentrations led to the depression and full blockade of pop-spike, that was associated with significant decrease in the pop-EPSP and fiber potential amplitudes. In contrast structurally related 4-aminopyridine evoked dose-dependent increase in both pop-EPSP and pop-spike amplitudes with all the concentrations tested (0.05-1000 microM), this facilitation was transformed into epileptiform response with 4-aminopyridine concentration about 500 microM. Possible mechanisms of drug actions on hippocampal neuron reactivity are discussed. It is suggested that amiridin might turn to be as effective as tacrine in symptomatic treatment of Alzheimer disease.

[Effect of kyotorphin on the reactivity of hippocampal neurons]. / Deistvie kiotorfina na reaktivnost' neironov gippokampa.

The effects of kyotorphin (Tyr-Arg) on CA1 and CA3 field responses were studied on rat hippocampal slice preparations. Slice perfusion with 10(-6)-10(-4) M of kyotorphin resulted in reactivity changes both in mossy fibers (CA3) and Schaffer collaterals (CA1). The principal effect was the increase in pop-spike amplitude. Kyotrophin (10(-6)-10(-5) M) and metenkephalin (10(-7)-10(-6) M) were found to produce similar reactivity changes (facilitation) in CA1 region of most preparations. However, kyotorphin effect, in contrast to enkephalin-induced facilitation was not blocked by naloxone. The data suggest that the mechanisms of kyotorphin action in the hippocamp are not related to endogenous enkephalin release.

Effects of beta-casomorphin on dentate hippocampal field potentials in freely moving rats.

Intracerebroventricular administration of 166 nmoles of the exogenic opioid beta-casomorphin (5) produced a potent and reversible depression of the compound action potential evoked in dentate granule cells by stimulation of the medial perforant path, whereas the extracellularly recorded excitatory postsynaptic potential is left unchanged. This in vivo effect of beta-casomorphin was obviously different from those observed previously in the CA 1 region in hippocampal slice experiments. The results suggest that more than one opioid mechanism determines the granule cell excitability. Some of the possible mechanisms involved in the effects of beta-casomorphins in the hippocampus are briefly discussed.