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Nail Burnashev

Publications and source records attributed to Nail Burnashev.

8 recordsLinked to original sources
PubMed2006

Cannabinoids modulate the P-type high-voltage-activated calcium currents in purkinje neurons.

Endocannabinoids released by postsynaptic cells inhibit neurotransmitter release in many central synapses by activating presynaptic cannabinoid CB1 receptors. In particular, in the cerebellum, endocannabinoids inhibit synaptic transmission at granule cell to Purkinje cell synapses by modulating presynaptic calcium influx via N-, P/Q-, and R-type calcium channels. Using whole cell patch-clamp techniques, we show that in addition to this presynaptic action, both synthetic and endogenous cannabinoids inhibit P-type calcium currents in isolated rat Purkinje neurons independent of CB1 receptor activation. The IC50 for the anandamide (AEA)-induced inhibition of P-current peak amplitude was 1.04 +/- 0.04 microM. In addition, we demonstrate that all the tested cannabinoids in a physiologically relevant range of concentrations strongly accelerate inactivation of P currents. The effects of AEA cannot be attributed to the metabolism of AEA because a nonhydrolyzing analogue of AEA, methanandamide inhibited P-type currents with a similar efficacy. All effects of cannabinoids on P-type Ca2+ currents were insensitive to antagonists of CB1 cannabinoid or vanilloid TRPV1 receptors. In cerebellar slices, WIN 55,212-2 significantly affected spontaneous firing of Purkinje neurons in the presence of CB1 receptor antagonist, in a manner similar to that of a specific P-type channel antagonist, indicating a possible functional implication of the direct effects of cannabinoids on P current. Taken together these findings demonstrate a functionally important direct action of cannabinoids on P-type calcium currents.

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PubMed2006

Non-fibrillar beta-amyloid abates spike-timing-dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors.

Cognitive decline in Alzheimer's disease (AD) stems from the progressive dysfunction of synaptic connections within cortical neuronal microcircuits. Recently, soluble amyloid beta protein oligomers (Abeta(ol)s) have been identified as critical triggers for early synaptic disorganization. However, it remains unknown whether a deficit of Hebbian-related synaptic plasticity occurs during the early phase of AD. Therefore, we studied whether age-dependent Abeta accumulation affects the induction of spike-timing-dependent synaptic potentiation at excitatory synapses on neocortical layer 2/3 (L2/3) pyramidal cells in the APPswe/PS1dE9 transgenic mouse model of AD. Synaptic potentiation at excitatory synapses onto L2/3 pyramidal cells was significantly reduced at the onset of Abeta pathology and was virtually absent in mice with advanced Abeta burden. A decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/N-methyl-D-aspartate (NMDA) receptor-mediated current ratio implicated postsynaptic mechanisms underlying Abeta synaptotoxicity. The integral role of Abeta(ol)s in these processes was verified by showing that pretreatment of cortical slices with Abeta((25-35)ol)s disrupted spike-timing-dependent synaptic potentiation at unitary connections between L2/3 pyramidal cells, and reduced the amplitude of miniature excitatory postsynaptic currents therein. A robust decrement of AMPA, but not NMDA, receptor-mediated currents in nucleated patches from L2/3 pyramidal cells confirmed that Abeta(ol)s perturb basal glutamatergic synaptic transmission by affecting postsynaptic AMPA receptors. Inhibition of AMPA receptor desensitization by cyclothiazide significantly increased the amplitude of excitatory postsynaptic potentials evoked by afferent stimulation, and rescued synaptic plasticity even in mice with pronounced Abeta pathology. We propose that soluble Abeta(ol)s trigger the diminution of synaptic plasticity in neocortical pyramidal cell networks during early stages of AD pathogenesis by preferentially targeting postsynaptic AMPA receptors.

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PubMed2005

Glycine receptors in CNS neurons as a target for nonretrograde action of cannabinoids.

At many central synapses, endocannabinoids released by postsynaptic cells act retrogradely on presynaptic G-protein-coupled cannabinoid receptors to inhibit neurotransmitter release. Here, we demonstrate that cannabinoids may directly affect the functioning of inhibitory glycine receptor (GlyR) channels. In isolated hippocampal pyramidal and Purkinje cerebellar neurons, endogenous cannabinoids anandamide and 2-arachidonylglycerol, applied at physiological concentrations, inhibited the amplitude and altered the kinetics of rise time, desensitization, and deactivation of the glycine-activated current (I(Gly)) in a concentration-dependent manner. These effects of cannabinoids were observed in the presence of cannabinoid CB1/CB3, vanilloid receptor 1 antagonists, and the G-protein inhibitor GDPbetaS, suggesting a direct action of cannabinoids on GlyRs. The effect of cannabinoids on I(Gly) desensitization was strongly voltage dependent. We also demonstrate that, in the presence of a GABA(A) receptor antagonist, GlyRs may contribute to the generation of seizure-like activity induced by short bursts (seven stimuli) of high-frequency stimulation of inputs to hippocampal CA1 region, because this activity was diminished by selective GlyR antagonists (strychnine and ginkgolides B and J). The GlyR-mediated rhythmic activity was also reduced by cannabinoids (anandamide) in the presence of a CB1 receptor antagonist. These results suggest that the direct inhibition of GlyRs by endocannabinoids can modulate the hippocampal network activity.

Animals↗
PubMed2005

Presynaptic Ca2+ dynamics, Ca2+ buffers and synaptic efficacy.

In synapses neurotransmitter release is triggered by elevation of Ca2+ concentration at a Ca2+ sensor of the release machinery. The Ca2+ concentration at the release site at the given time point is determined by Ca2+ dynamics within presynaptic terminal. It depends on a source of Ca2+ (usually voltage-gated Ca2+ channels), diffusional distance between the source of Ca2+ and the Ca2+ sensor and Ca2+ buffering by endogenous Ca2+ buffers. In many synapses transmitter release can be enhanced (facilitated) during repetitive activity of neurons. The main source of facilitation is activity-dependent increase of Ca2+ concentration at the release site. Several mechanisms of facilitation have been proposed, namely, accumulation of residual Ca2+, multi-site (X receptor) mechanism and partial Ca2+ buffer saturation mechanism. In this review we discuss theoretical and experimental evidence in favor of one or the other of proposed mechanisms.

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PubMed2004

NMDA receptors induce somatodendritic secretion in hypothalamic neurones of lactating female rats.

Many neurones in the mammalian brain are known to release the content of their vesicles from somatodendritic locations. These vesicles usually contain retrograde messengers that modulate network properties. The back-propagating action potential is thought to be the principal physiological stimulus that evokes somatodendritic release. In contrast, here we show that calcium influx through NMDA receptor (NMDAR) channels, in the absence of postsynaptic cell firing, is also able to induce vesicle fusion from non-synaptic sites in nucleated outside-out patches of dorsomedial supraoptic nucleus (SON) neurones of adult female rats, in particular during their reproductive stages. The physiological significance of this mechanism was characterized in intact brain slices, where NMDAR-mediated release of oxytocin was shown to retrogradely inhibit presynaptic GABA release, in the absence of postsynaptic cell firing. This implies that glutamatergic synaptic input in itself is sufficient to elicit the release of oxytocin, which in turn acts as a retrograde messenger leading to the depression of nearby GABA synapses. In addition, we found that during lactation, when oxytocin demand is high, NMDA-induced oxytocin release is up-regulated compared to that in non-reproductive rats. Thus, in the hypothalamus, local signalling back and forth between pre- and postsynaptic compartments and between different synapses may occur independently of the firing activity of the postsynaptic neurone.

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PubMed2003

A juvenile form of postsynaptic hippocampal long-term potentiation in mice deficient for the AMPA receptor subunit GluR-A.

In adult mice, long-term potentiation (LTP) of synaptic transmission at CA3-to-CA1 synapses induced by tetanic stimulation requires L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors containing GluR-A subunits. Here, we report a GluR-A-independent form of LTP, which is comparable in size to LTP in wild-type mice at postnatal day 14 (P14) but diminishes between P14 and P42 in brain slices of GluR-A-deficient mice. The GluR-A-independent form of LTP is sensitive to D(-)-2-amino-5-phosphonopentanoic acid (D-AP5), but lacks short-term potentiation (STP) and can also be observed in the pairing induction protocol. As judged by unaltered paired-pulse facilitation, this LTP form is postsynaptically expressed despite depleted extrasynaptic AMPA receptor pools with reduced levels of GluR-B, which accumulates in somata and synapses of CA1 pyramidal neurons in GluR-A-deficient mice. Our results show that in the developing hippocampus synaptic plasticity can be expressed by AMPA receptors lacking the GluR-A subunit.

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PubMed2003

Ca2+ buffer saturation underlies paired pulse facilitation in calbindin-D28k-containing terminals.

Ca2+ buffer saturation was proposed as a mechanism of paired pulse facilitation (PPF). However, whether it operates under native conditions remained unclear. Here we show that saturation of the endogenous fast Ca2+ buffer calbindin-D28k (CB) plays a major role in PPF at CB-containing synapses. Paired recordings from synaptically connected interneurons and pyramidal neurons in the mouse neocortex revealed that dialysis increased the amplitude of the first response and decreased PPF. Loading the presynaptic terminals with BAPTA or CB rescued the effect of the CB washout. We extended the study to the CB-positive facilitating excitatory mossy fiber-CA3 pyramidal cell synapse. The effects of different extracellular Ca2+ concentrations and of EGTA indicated that PPF in CB-containing terminals depended on Ca2+ influx rather than on the initial release probability. Experiments in CB knockout mice confirmed that buffer saturation is a novel basic presynaptic mechanism for activity-dependent control of synaptic gain.

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