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ABSTRACT: The transient receptor potential vanilloid type 1 (TRPV1) channel is a well recognized polymodal signal detector that is activated by painful stimuli such as capsaicin. Here, we show that TRPV1 is expressed in the lateral nucleus of the amygdala (LA). Despite the fact that the central amygdala displays the highest neuronal density, the highest density of TRPV1 labeled neurons was found within the nuclei of the basolateral complex of the amygdala. Capsaicin specifically changed the magnitude of long-term potentiation (LTP) in the LA in brain slices of mice depending on the anesthetic (ether, isoflurane) used before euthanasia. After ether anesthesia, capsaicin had a suppressive effect on LA-LTP both in patch clamp and in extracellular recordings. The capsaicin-induced reduction of LTP was completely blocked by the nitric oxide synthase (NOS) inhibitor L-NAME and was absent in neuronal NOS as well as in TRPV1 deficient mice. The specific antagonist of cannabinoid receptor type 1 (CB1), AM 251, was also able to reduce the inhibitory effect of capsaicin on LA-LTP, suggesting that stimulation of TRPV1 provokes the generation of anandamide in the brain which seems to inhibit NO synthesis. After isoflurane anesthesia before euthanasia capsaicin caused a TRPV1-mediated increase in the magnitude of LA-LTP. Therefore, our results also indicate that the appropriate choice of the anesthetics used is an important consideration when brain plasticity and the action of endovanilloids will be evaluated. In summary, our results demonstrate that TRPV1 may be involved in the amygdala control of learning mechanisms.
PLoS ONE 01/2011; 6(1):e16116. · 4.09 Impact Factor
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ABSTRACT: Recent evidence suggests that lithium, which is used in the treatment of bipolar disorders, may act by influencing AMPAR properties at central glutamatergic synapses. While it is clear that lithium potentiates recombinant AMPAR responses in a subunit specific way, the origin of this potentiation is not known. We examined the effects of lithium on native AMPAR channels in CA1 pyramidal cells in hippocampal slices where AMPARs are expected to be associated with auxiliary subunits. We found that lithium produced a selective increase in single-channel open probability (P(open)), with little effect on single-channel conductance or burst length. From the present and previous finding it is likely that lithium causes a reduction in the time to recovery from desensitization, resulting in the observed increase in P(open). This would be consistent with the view that lithium acts like certain other allosteric AMPAR modulators to reduce the time spent in the desensitized state, but differs from those that act by slowing dissociation of glutamate.
The Journal of Physiology 10/2010; 588(Pt 20):3933-41. · 4.72 Impact Factor
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ABSTRACT: The lateral nucleus of the amygdala (LA) is implicated in emotional and social behaviors. We recently showed that in horizontal brain slices, activation of NMDA receptors (NMDARs) is a requirement for persistent synaptic alterations in the LA, such as long-term potentiation (LTP) and long-term depression (LTD). In the LA, NR2A- and NR2B-type NMDRs coexist in synapses of LA projection neurons. We assessed the contribution of the two NMDAR subtypes to LA-LTP and LA-LTD in adult mouse brain slices by different induction protocols and by different inputs to LA neurons in the presence of different NMDAR subunit antagonists. In general, our results indicate that both NR2A and NR2B subunits are required for the formation of LA-LTP and LA-LTD. The abolishment or reduction of plasticity changes by these compounds could be due to the reduction in calcium influx via NMDARs. We also show, to our knowledge for the first time, that paired-pulse (40-msec interstimulus interval), low-frequency stimulation of external capsule fibers causes stable LTD. Rather than resulting from exclusive roles of the NMDAR subtypes, the synaptic plasticity response in the amygdala appears to be directed by the pattern of synaptic activation and the used inputs, which recruit the major NMDAR subtypes to variable extents.
Learning & memory (Cold Spring Harbor, N.Y.) 02/2009; 16(6):395-405. · 4.08 Impact Factor
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Abdolrahman S Nateri,
Gennadij Raivich, Christine Gebhardt,
Clive Da Costa,
Heike Naumann,
Martin Vreugdenhil,
Milan Makwana,
Sebastian Brandner,
Ralf H Adams,
John G R Jefferys,
Oliver Kann,
Axel Behrens
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ABSTRACT: The ERK MAPK signalling pathway is a highly conserved kinase cascade linking transmembrane receptors to downstream effector mechanisms. To investigate the function of ERK in neurons, a constitutively active form of MEK1 (caMEK1) was conditionally expressed in the murine brain, which resulted in ERK activation and caused spontaneous epileptic seizures. ERK activation stimulated phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) and augmented NMDA receptor 2B (NR2B) protein levels. Pharmacological inhibition of NR2B function impaired synaptic facilitation in area cornus ammonicus region 3 (CA3) in acute hippocampal slices derived from caMEK1-expressing mice and abrogated epilepsy in vivo. In addition, expression of caMEK1 caused phosphorylation of the transcription factor, cAMP response element-binding protein (CREB) and increased transcription of ephrinB2. EphrinB2 overexpression resulted in increased NR2B tyrosine phosphorylation, which was essential for caMEK1-induced epilepsy in vivo, since conditional inactivation of ephrinB2 greatly reduced seizure frequency in caMEK1 transgenic mice. Therefore, our study identifies a mechanism of epileptogenesis that links MAP kinase to Eph/Ephrin and NMDA receptor signalling.
The EMBO Journal 12/2007; 26(23):4891-901. · 9.20 Impact Factor
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ABSTRACT: We have determined the functional properties of single AMPA receptor (AMPAR) and kainate receptor channels present in CA1 cells in hippocampal slices, to shed light on the relationship between single-channel behaviour and synaptic currents in these cells. To derive basic properties of AMPA and kainate channels activated by their excitatory transmitter, we examined outside-out patches exposed to glutamate. The kainate agonist SYM 2081, was used to confirm the presence of kainate receptors. Channels activated by glutamate or SYM 2081 exhibited conductance levels of 2-20 pS. Properties of single channels depended on the glutamate or AMPA concentration used. We observed a marked increase in mean channel conductance (gamma) from gamma = 6.9, to 11.2 pS, when glutamate was increased from 10 mum to 10 mm. The kinetic behaviour of AMPAR channels was also influenced by agonist concentration, with an increase in 'bursty' events at higher concentrations. In contrast, kainate channels were characterized by brief openings without bursts. Consistent with the view that 'bursty' events arose from AMPARs, these openings decreased in the presence of the AMPAR blocker GYKI 53655. Furthermore, our experiments revealed a concentration-dependent increase in the number of conductance states during an individual AMPAR opening; AMPAR channels displayed up to four distinct levels. Our results are consistent with the view that the AMPAR channel conductance depends on the number of transmitter molecules bound in CA1 cells. We consider the implications of these findings for the change in EPSC properties during long-term potentiation (LTP).
The Journal of Physiology 07/2006; 573(Pt 2):371-94. · 4.72 Impact Factor
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ABSTRACT: In layer III of the medial entorhinal cortex (mEC), a region that is especially prone to cell damage in Alzheimer's disease, schizophrenia and epilepsy, effects of blocking glutamate uptake on excitatory synaptic transmission were studied. Two competitive glutamate transporter antagonists, TBOA and tPDC, reduced the amplitude of pharmacologically isolated AMPAR and NMDAR mediated EPSPs/EPSCs without changing the time course of the events. This effect was mimicked by tACPD, an agonist of groups I and II metabotropic glutamate receptors (mGluRs). The competitive groups I and II mGluR antagonist MCPG blocked the depression of the EPSC amplitude induced by tACPD and also prevented the effect of either TBOA or tPDC. Furthermore, EGLU, which selectively antagonizes group II mGluRs, blocked the effect of tPDC and LY3414965, a specific group I mGluR antagonist, abolished the reduction of amplitude caused by TBOA. Additionally, application of TBOA increased the paired-pulse index, suggesting a presynaptic mechanism for the depression of EPSP/EPSC amplitude. The present data suggest that glutamate transporters and group I/II mGluRs regulate excitatory synaptic transmission in the mEC. Presynaptic mGluRs may limit excessive glutamate accumulation if uptake becomes compromised.
Brain Research 12/2004; 1027(1-2):151-60. · 2.73 Impact Factor
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ABSTRACT: Several lines of evidence indicate a substantial contribution of kainate receptors to temporal lobe seizures. The activation of kainate receptors located on hippocampal inhibitory interneurons was shown to reduce GABA release. A reduced GABA release secondary to kainate receptor activation could contribute to an enhanced seizure susceptibility. As the dentate gyrus serves a pivotal gating function in the spread of limbic seizures, we tested the role of kainate receptors in the regulation of GABA release in the dentate gyrus of control and kindled animals. Application of glutamate (100 micro m) in the presence of the NMDA receptor antagonist d-APV and the AMPA receptor antagonist, SYM 2206 caused a slight depression of evoked monosynaptic inhibitory postsynaptic currents (IPSCs) in control, but a substantial decrease in kindled dentate granule cells. The observation that kainate receptor activation altered paired-pulse depression and reduced the frequency of TTX-insensitive miniature IPSCs without affecting their amplitude is consistent with a presynaptic action on the inhibitory terminal to reduce GABA release. In kindled preparations, neither glutamate (100 micro m) nor kainate (10 micro m) applied in a concentration known to depolarize hippocampal interneurons led to an increase of the TTX-sensitive spontaneous IPSC frequency nor to changes of the postsynaptic membrane properties. Consistently, the inhibitory effect on evoked IPSCs was not affected by the presence of the GABAB receptor antagonist, CGP55845A, thus excluding a depression by an enhanced release of GABA acting on presynaptic GABAB receptors. The enhanced inhibition of GABA release following presynaptic kainate receptor activation favours a use-dependent hyperexcitability in the epileptic dentate gyrus.
European Journal of Neuroscience 10/2002; 16(5):861-7. · 3.63 Impact Factor
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ABSTRACT: Hypoxia leads to a rapid increase in vesicular release of glutamate. In addition, hypoxic glutamate release might be caused by reversed operation of neuronal glutamate transporters. An increase in extracellular glutamate concentration might be an important factor in generating anoxic depolarizations (AD) and subsequent neuronal damage. To study the AD and the vesicular release in hippocampal slices from CD1 wild-type mice and mice in which the neuronal glutamate transporter excitatory amino acid carrier 1 (EAAC1) had been knocked out, the authors performed recordings of field potentials and patch clamp recordings of CA1 pyramidal cells. Latency to anoxic depolarizations was enhanced in EAAC1-/- mice, whereas the hypoxia-induced increase in miniature excitatory postsynaptic current frequency occurred with similarly short latencies and to a similar extent in control and mutated animals. Additional block of glial glutamate uptake with TBOA (dl-threo-beta-benzyloxyaspartate), a nontransportable and potent inhibitor, dramatically reduced the latency to onset of AD and abolished the difference between wild-type mice and EAAC1-/- mice. The authors conclude that the neuronal glutamate transporter greatly influences the latency to generation of AD. Because ADs are not prevented in EAAC1-deficient mice, vesicular release mechanisms also seem to be involved. They become prominent when glial glutamate transport is blocked.
Journal of Cerebral Blood Flow & Metabolism 06/2002; 22(5):569-75. · 5.01 Impact Factor
