生物谷報道：激發(fā)性突觸（促使目標(biāo)神經(jīng)細(xì)胞更多被激發(fā)的神經(jīng)細(xì)胞連接）會隨著持續(xù)的使用而變得更強(qiáng)。這一被稱為LTP（長期增強(qiáng)）的過程與學(xué)習(xí)和記憶有關(guān),。用大鼠的大腦所做的一項體外研究表明,，這種激發(fā)性增強(qiáng)會在大鼠大腦的ventraltegmental區(qū)域（該區(qū)域已知與藥物上癮有關(guān)）中的相鄰抑制性突觸上產(chǎn)生鏡像作用，嗎啡能夠抑制在抑制性突觸上的長期增強(qiáng),，說明破壞神經(jīng)激發(fā)和抑制之間的平衡也許能夠增強(qiáng)上癮早期階段多巴胺能神經(jīng)元的激發(fā),。因此，以GABAa受體為目標(biāo)也許是解決上癮性藥物的上癮效應(yīng)的一種手段,。這項研究結(jié)果發(fā)表于最新一期的《Nature》雜志上,。

FIGURE 1. GABAergic synapses on dopamine neurons are potentiated after HFS.
a, LTPGABA in a dopamine neuron using whole-cell recording methods. HFS was delivered at the arrow. Inset: averaged IPSCs before (black) and 25 min after HFS (grey). In this and all figures, ten consecutive IPSCs from each condition were averaged for illustration. Calibration for insets: 10 ms, 50 pA. The dotted line in this and other figures is an approximation of the mean response before HFS. b, Average of 71 experiments from dopamine cells. LTPGABA was not triggered in all cells, but data from all cells are included in this and subsequent graphs. The dotted line represents the mean normalized IPSC value before HFS. c, LTPGABA in a dopamine neuron using gramicidin-perforated patch recording. Inset: averaged IPSCs before (black) and 25 min after HFS (grey). d, Average of eight gramicidin-perforated patch experiments from dopamine cells (LTPGABA, 146   4% of pre-HFS values; n  =  8). All cells but one exhibited LTP. e, LTPGABA in dopamine cells was accompanied by a decrease in the paired-pulse ratio (PPR, IPSC2/IPSC1; n  =  35). f, LTPGABA was accompanied by an increase in 1/CV2 (squared mean IPSC amplitude divided by IPSC variance; n  =  35). Error bars in all figures indicate means   s.e.m.

原文出處：

Volume 446 Number 7139

Opioids block long-term potentiation of inhibitory synapses p1086
Fereshteh S. Nugent, Esther C. Penick & Julie A. Kauer

doi:10.1038/nature05726

First paragraph | Full Text | PDF (1,370K) | Supplementary information

See also: Editor's summary

作者簡介：

Julie Kauer, Ph.D.   

Professor of Medical Science

Brown University

Education

Ph.D., Yale University, 1986

Research

My laboratory focuses on understanding molecular mechanisms involved in information storage and modulation of excitability in the brain, using electrophysiological techniques in brain slices. Our efforts are concentrated in two brain regions, the hippocampus and the ventral tegmental area (VTA). The hippocampus is required for normal formation of long-term memory, and the cellular mechanisms that underlie information storage in the vertebrate brain were first observed and have been intensively studied in the hippocampus. In recent years, my laboratory pursued two major goals: first, to understand how the excitability of neuronal circuits in the hippocampus is controlled, and second, to elucidate basic molecular mechanisms that underlie synaptic plasticity in the central nervous system. We have also begun investigating synaptic plasticity in the ventral tegmental area (VTA), a mesencephalic region that forms the origination zone of the brain's reward system. This region is essential in the development of drug addiction. The lab is currently testing the idea that drugs of abuse act directly in the VTA to cause long-term synaptic modifications that could mediate the intense craving produced by these drugs.

Molecular mechanisms underlying synaptic plasticity:
The cellular basis of information storage is likely to involve long-term alterations in the strength of synapses, the connections between neurons. Synaptic modifications in the hippocampus are likely to underlie both physiological mechanisms used for memory formation and pathological changes associated with epileptic activity. The most well-studied examples of adult synaptic plasticity are called long-term potentiation (LTP) and long-term depression (LTD). Several aspects of the molecular processes that underlie LTP and LTD are understood for the excitatory neurons of hippocampus, while other important features are still unknown.

One recent project has been carried out in collaboration with Dr. Michael Ehlers at Duke University. Postsynaptic insertion of AMPA receptors in synaptic regions is responsible for rapid increases in synaptic strength at CA3-CA1 hippocampal synapses. Using viral constructs that interfere with the trafficking of membrane-bound proteins, we have asked which intracellular compartment contributes the AMPA receptors that are inserted at synapses during LTP. We have identified a particular endosomal compartment as a necessary component of the pathway for LTP at CA1 synapses, work that appeared in Science. In our continuing collaborative work, we will be combining molecular approaches with cellular physiology in brain slices to manipulate "real" neurons but elucidate molecular mechanisms.

We also have been comparing excitatory synapses from the same population of glutamate afferents onto two distinct postsynaptic target cells, the CA1 pyramidal cells and CA1 GABAergic interneurons. In contrast to excitatory synapses on pyramidal cells, synapses on interneurons are made on dendritic shafts rather than spines, often lack GluR2 (which when absent produces Ca2+ permeable AMPARs), and lack several key kinases and phosphatases involved in synaptic plasticity, including CaMKII and phosphoprotein phosphatase 2B. We have recently characterized an endocannabinoid-mediated form of long-term depression observed at synapses on interneurons but not on pyramidal cell neighbors.

Synaptic plasticity in midbrain dopamine neurons and drug addiction:
Recently my lab has focused on the essentially permanent changes in the nervous system that accompany drug addiction because these long-term changes represent a form of neural plasticity that is tightly correlated with behavior. Modifications of midbrain synapses in the reward pathway represent a possible initiation site for drugs of abuse. More generally, the ability of the brain's reward pathway to undergo plastic changes is important, since this type of 'learning' is certainly necessary for survival.

Drug addiction and the brain's response to drug abuse are complex processes likely to require interactions among many brain regions. However, careful in vivo analysis has defined the ventral tegmental area (VTA) as necessary and sufficient for the initiation of one aspect of drug abuse, sensitization (an animal model of drug craving). My hypothesis is that synapses onto dopamine neurons in VTA undergo long-term changes in strength, like those described in hippocampus and elsewhere. We have found that synaptic plasticity indeed occurs at these synapses. Moreover, LTD is entirely blocked during exposure to amphetamine, a highly addictive drug. This was the first demonstration that an addictive drug can block synaptic plasticity selectively in pathways that mediate reward. We and others have also found that administration of multiple addictive drugs in vivo produces profound increases in synaptic strength at these synapses. Most recently, we have identified an entirely novel form of long-term potentiation of GABAergic synapses onto dopamine cells that may contribute to long-lasting changes in VTA function. Our goal is to determine whether addictive drugs from chemically distinct classes (e.g. psychostimulants, morphine, nicotine) favor the development of abnormal synaptic plasticity either acutely, or over time in vivo. This model system linking synaptic plasticity and behavior has many advantages over the more complex behaviors mediated by hippocampal and cortical circuits, and I believe that the links we can make in the VTA may be used more generally throughout the brain during learning and adaptive responses.