by 刘运辉 | 2015-07-07
Salk生物研究所Stephen F. Heinemann教授发现胶质细胞参与认知与记忆相关神经环路的调节（PNAS, 2014）。与此密切相关的一项研究表明，利用光基因激活胶质细胞释放乳酸（L-Lactate）能够兴奋蓝斑核神经元来释放去甲肾上腺素，提示乳酸可能作为一种胶质递质参与神经环路活动的调控（Nature Communications, 2014）。神经元利用葡萄糖产能具有三条途径，其中一条是通过胶质细胞中的乳酸脱氢酶（LDH）将葡萄糖转化为乳酸，然后提供给神经元利用。日本岗山大学Tsuyoshi Inoue教授研究组发现通过抑制胶质细胞中的LDH，降低这条代谢途径的效能，能有效治疗癫痫发作，并据此开发能够用于治疗癫痫发作的新药（Science, 2015）。
1. 论文题目：Astrocytes contributeto gamma oscillations and recognition memory. PNAS. 2014 E3343-52
原文摘要：Glial cells are anintegral part of functional communication in the brain. Here we showthat astrocytes contribute to the fast dynamics of neuralcircuits that underlie normal cognitive behaviors. In particular, we found thatthe selective expression of tetanus neurotoxin (TeNT)in astrocytessignificantly reduced the duration ofcarbachol-induced gamma oscillations in hippocampal slices.These data prompted us to develop a novel transgenic mouse model, specificallywith inducible tetanus toxin expression in astrocytes. In this in vivomodel, we found evidence of a marked decrease in electroencephalographic (EEG)power in the gamma frequency range in awake-behaving mice, whereas neuronalsynaptic activity remained intact. The reduction incortical gamma oscillations was accompaniedby impaired behavioral performance in the novel object recognitiontest,whereas other forms of memory, including working memory and fearconditioning, remained unchanged. These results support a key roleforgamma oscillations in recognition memory. Both EEGalterations and behavioral deficits in novel object recognition werereversed by suppression of tetanus toxin expression. These data reveal anunexpected role for astrocytes as essential contributors toinformation processing and cognitive behavior.
2. Lactate-mediatedglia-neuronal signaling in the mammalian brain. Nature Communications. 2014;5:3284
原文摘要：Astrocytes produce andrelease L-lactate as a potential source of energy for neurons. Here we presentevidence that L-lactate, independently of its caloric value, serves as anastrocytic signalling molecule in the locus coeruleus (LC). The LC isthe principal source of norepinephrine to the frontalbrain and thus one ofthe most influential modulatory centers of the brain. Optogeneticallyactivated astrocytes release L-lactate, which excites LC neurons and triggersrelease of norepinephrine. Exogenous L-lactate within the physiologicallyrelevant concentration range mimics these effects. L-lactate effects areconcentration-dependent, stereo-selective, independent of L-lactate uptake intoneurons and involve a cAMP-mediated step. In vivo injections of L-lactate inthe LC evokes arousal similar to the excitatory transmitter, L-glutamate. Ourresults imply the existence of an unknown receptor for this \'glio-transmitter\'.
3. Targeting LDH enzymes witha stiripentol analog to treat epilepsy. Science. 2015347:1362-7.
原文摘要：Neuronal excitation isregulated by energy metabolism, and drug-resistant epilepsy can besuppressed by special diets. Here, we report that seizures and epileptiformactivity are reduced by inhibition of the metabolic pathway via lactatedehydrogenase (LDH), a component of the astrocyte-neuron lactate shuttle.Inhibition of the enzyme LDH hyperpolarized neurons, which wasreversed by the downstream metabolite pyruvate. LDH inhibition alsosuppressed seizures in vivo in a mouse model of epilepsy. We further foundthat stiripentol, a clinically used antiepileptic drug, isan LDH inhibitor. By modifying its chemical structure, we identifieda previously unknown LDH inhibitor, which potently suppressedseizures in vivo. We conclude that LDH inhibitors are a promising newgroup of antiepileptic drugs.
4. Activated astrocytes enhance the dopaminergic differentiation of stem cells and promote brain repair throughbFGF. Nature Communications. 201417;5:5627.
原文摘要：Astrocytes provideneuroprotective effects against degeneration of dopaminergic (DA)neurons and play a fundamental role in DA differentiation ofneural stem cells. Here we show that light illumination of astrocytes expressingengineered channelrhodopsin variant (ChETA) can remarkablyenhance therelease of basic fibroblast growth factor (bFGF) andsignificantly promote the DA differentiation of humanembryonic stem cells (hESCs) in vitro. Light activation oftransplanted astrocytes in the substantia nigra (SN) alsoupregulates bFGF levels in vivo and promotes the regenerative effectsof co-transplanted stem cells. Importantly, upregulationof bFGF levels, by specific light activation ofendogenous astrocytes in the SN, enhances theDA differentiation of transplanted stem cells andpromotes brain repair in a mouse model of Parkinson\'s disease(PD). Our study indicates that astrocyte-derived bFGF is required forregulation of DA differentiation of the stem cells andmay provide a strategy targeting astrocytesfor treatment of PD.