Modulation of hippocampal plasticity in learning and memory

Synaptic plasticity plays a central role in the study of neural mechanisms of learning and memory. Plasticity rules are not invariant over time but are under neuromodulatory control, enabling behavioral states to influence memory formation. Neuromodulation controls synaptic plasticity at network level by directing information flow, at circuit level through changes in excitation/inhibition balance, and at synaptic level through modulation of intracellular signaling cascades. Although most research has focused on modulation of principal neurons, recent progress has uncovered important roles for interneurons in not only routing information, but also setting conditions for synaptic plasticity. Moreover, astrocytes have been shown to both gate and mediate plasticity. These additional mechanisms must be considered for a comprehensive mechanistic understanding of learning and memory.     

神经细胞粘附分子与记忆

记忆的形成阶段包含着神经元突触的可塑性变化过程.近年来的研究表明,神经细胞粘附分子可同时增进突触的可塑性和维持突触结构的稳定性.许多研究证实神经细胞粘附分子对与学习和记忆相关的过程起着一定的调节作用.     

神经胶质细胞与突触可塑性研究新进展

突触的可塑性是研究学习与记忆的基础,很长时间以来人们对突触的可塑性研究主要集中在神经元和突触上;而胶质细胞的作用较少受到注意。最近的研究发现胶质细胞也参与突触的构成并影响突触的活动。研究表明中枢神经系统中的胶质细胞包括星形胶质细胞、小胶质细胞和少突胶质细胞可分别通过谷氨酸、丝氨酸、甘氨酸、ATP等信号调节突触的可塑性,从而为突触的可塑性研究提供了新的思路和方向,并有助于阐明突触的发生以及学习与记忆的机制。     

Cdk5: a novel role in learning and memory

Learning and memory are processes by which organisms acquire, retain and retrieve information. They result in modifications of behavior in response to new or previously encountered stimuli thereby enabling adaptation to a permanently changing environment. Protein phosphorylation has long been known to play a key role in triggering synaptic changes underlying learning and memory. Although intracellular phosphorylation and dephosphorylation is orchestrated by a complex network of interactions between a number of protein kinases and phosphatases, significant advances in the understanding of neuronal mechanisms underlying learning and memory have been achieved by investigating the actions of individual molecules under defined experimental conditions, brain areas, neuronal cells and their subcellular compartments. On the basis of these approaches, the cyclic AMP protein kinase (PKA), protein kinase C (PKC) and extracellularly regulated protein kinases 1 and 2 (Erk-1/2) have been identified as the core signaling pathways in memory consolidation. Here we review recent findings demonstrating an important novel role for Cdk5 in learning and memory. We suggest that some of the well-characterized roles of Cdk5 during neurodevelopmental processes, such as interactions with distinct cytoplasmic and synaptic target molecules, may be also involved in synaptic plasticity underlying memory consolidation within the adult central nervous system.     

GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity

AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these interacting proteins in regulating the AMPA receptor function during basal synaptic transmission and plasticity.     

Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity

The peripheral functions of hormones such as leptin, insulin and estrogens are well documented. An important and rapidly expanding field is demonstrating that as well as their peripheral actions, these hormones play an important role in modulating synaptic function and structure within the CNS. The hippocampus is a major mediator of spatial learning and memory and is also an area highly susceptible to epileptic seizure. As such, the hippocampus has been extensively studied with particular regard to synaptic plasticity, a process thought to be necessary for learning and memory. Modulators of hippocampal function are therefore of particular interest, not only as potential modulators of learning and memory processes, but also with regard to CNS driven diseases such as epilepsy. Hormones traditionally thought of as only having peripheral roles are now increasingly being shown to have an important role in modulating synaptic plasticity and dendritic morphology. Here we review recent findings demonstrating that a number of hormones are capable of modulating both these phenomena.Key words: synaptic plasticity, leptin, estrogen, insulin, hippocampus, LTD, LTP     

Hormonal regulation of hippocampal dendritic morphology and synaptic plasticity

The peripheral functions of hormones such as leptin, insulin and estrogens are well documented. An important and rapidly expanding field is demonstrating that as well as their peripheral actions, these hormones play an important role in modulating synaptic function and structure within the CNS. The hippocampus is a major mediator of spatial learning and memory and is also an area highly susceptible to epileptic seizure. As such, the hippocampus has been extensively studied with particular regard to synaptic plasticity, a process thought to be necessary for learning and memory. Modulators of hippocampal function are therefore of particular interest, not only as potential modulators of learning and memory processes, but also with regard to CNS driven diseases such as epilepsy. Hormones traditionally thought of as only having peripheral roles are now increasingly being shown to have an important role in modulating synaptic plasticity and dendritic morphology. Here we review recent findings demonstrating that a number of hormones are capable of modulating both these phenomena.     

表观遗传修饰在学习和记忆中的调节作用

学习和记忆行为是大脑的基本功能,它使得生物个体能够更好地适应环境的变化。揭示学习和记忆的分子生物学机制是现代神经生物学发展的目标之一。经过近40年的研究现已初步证实了突触可塑性在学习和记忆中所起的关键作用。而近年来的研究发现,表观遗传修饰对学习和记忆过程具有重要的调控作用。这一发现将有利于进一步揭示学习和记忆的复杂机制,并将为某些认知障碍性疾病的治疗提供新的思路。     

药物成瘾及成瘾记忆的研究现状

本文在介绍药物成瘾与学习和记忆密切相关的神经回路及共同分子机制的基础上,围绕学习和记忆在药物成瘾中的作用,综述了关联性学习与复吸,关联性学习与敏化,异常关联性学习与强迫性用药行为,关联性学习及成瘾记忆与成瘾,多重记忆系统与成瘾的发生发展等方面的研究进展,并强调了突触可塑性及成瘾记忆在药物成瘾中的重要性。在此基础上提出：作为慢性脑病的药物成瘾的形成过程的重要特征是它包含着信息的特殊学习类型。药物成瘾与依赖于多巴胺的关联性学习紊乱有密切关系。海马可能在成瘾中扮演重要角色。     

Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration

Mutations in presenilins are the major cause of familial Alzheimer's disease, but the pathogenic mechanism by which presenilin mutations cause memory loss and neurodegeneration remains unclear. Here we demonstrate that conditional double knockout mice lacking both presenilins in the postnatal forebrain exhibit impairments in hippocampal memory and synaptic plasticity. These deficits are associated with specific reductions in NMDA receptor-mediated responses and synaptic levels of NMDA receptors and alphaCaMKII. Furthermore, loss of presenilins causes reduced expression of CBP and CREB/CBP target genes, such as c-fos and BDNF. With increasing age, mutant mice develop striking neurodegeneration of the cerebral cortex and worsening impairments of memory and synaptic function. Neurodegeneration is accompanied by increased levels of the Cdk5 activator p25 and hyperphosphorylated tau. These results define essential roles and molecular targets of presenilins in synaptic plasticity, learning and memory, and neuronal survival in the adult cerebral cortex.     

Regulation of Calpain-2 in Neurons: Implications for Synaptic Plasticity

The family of calcium-dependent neutral proteases, calpains, was discovered more than 30 years ago, but their functional roles in the nervous system under physiological or pathological conditions still remain unclear. Although calpain was proposed to participate in synaptic plasticity and in learning and memory in the early 1980s, the precise mechanism regarding its activation, its target(s) and the functional consequences of its activation have remained controversial. A major issue has been the identification of roles of the two major calpain isoforms present in the brain, calpain-1 and calpain-2, and the calcium requirement for their activation, which exceeds levels that could be reached intracellularly under conditions leading to changes in synaptic efficacy. In this review, we discussed the features of calpains that make them ideally suited to link certain patterns of presynaptic activity to the structural modifications of dendritic spines that could underlie synaptic plasticity and learning and memory. We then summarize recent findings that provide critical answers to the various questions raised by the initial hypothesis, and that further support the idea that, in brain, calpain-2 plays critical roles in developmental and adult synaptic plasticity.     

Synaptic plasticity in drug reward circuitry

Drug addiction is a major public health issue worldwide. The persistence of drug craving coupled with the known recruitment of learning and memory centers in the brain has led investigators to hypothesize that the alterations in glutamatergic synaptic efficacy brought on by synaptic plasticity may play key roles in the addiction process. Here we review the present literature, examining the properties of synaptic plasticity within drug reward circuitry, and the effects that drugs of abuse have on these forms of plasticity. Interestingly, multiple forms of synaptic plasticity can be induced at glutamatergic synapses within the dorsal striatum, its ventral extension the nucleus accumbens, and the ventral tegmental area, and at least some of these forms of plasticity are regulated by behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the present data suggest that regulation of synaptic plasticity in reward circuits is a tractable candidate mechanism underlying aspects of addiction.     

NMDA受体信号复合体中蛋白质的相互作用

谷氨酸能兴奋性突触的突触后密集区(postsynaptic density,PSD)包含多种受体蛋白、骨架蛋白和信号蛋白,它们通过分子中特定的结构域相互识别并动态地结合,形成多个信号复合体,参与突触后受体功能的调节及其下游特异性信号转导通路的激活。其中,NMDA受体信号复合体中蛋白质-蛋白质的相互作用及其调控机制的阐明,对于深入了解神经发育、突触可塑性、兴奋性毒性等生理病理的分子机制有重要意义。     

CPEB4 Knockout Mice Exhibit Normal Hippocampus-Related Synaptic Plasticity and Memory

Regulated RNA translation is critical to provide proteins needed to maintain persistent modification of synaptic strength, which underlies the molecular basis of long-term memory (LTM). Cytoplasmic polyadenylation element-binding proteins (CPEBs) are sequence-specific RNA-binding proteins and regulate translation in various tissues. All four CPEBs in vertebrates are expressed in the brain, including the hippocampal neurons, suggesting their potential roles in translation-dependent plasticity and memory. Although CPEB1 and CPEB3 have been shown to control specific kinds of hippocampus-related LTM, the role of CPEB2 and CPEB4 in learning and memory remains elusive. Thus, we generated CPEB4 knockout (KO) mice and analyzed them using several behavioral tests. No difference was found in the anxiety level, motor coordination, hippocampus-dependent learning and memory between the KO mice and their wild-type (WT) littermates. Electrophysiological recordings of multiple forms of synaptic plasticity in the Schaffer collateral pathway-CA1 neurons also showed normal responses in the KO hippocampal slices. Morphological analyses revealed that the CPEB4-lacking pyramidal neurons possessed slightly elongated dendritic spines. Unlike its related family members, CPEB1 and CPEB3, CPEB4 seems to be dispensable for hippocampus-dependent plasticity, learning and memory.     

A synaptic model for pain: long-term potentiation in the anterior cingulate cortex

Investigation of molecular and cellular mechanisms of synaptic plasticity is the major focus of many neuroscientists. There are two major reasons for searching new genes and molecules contributing to central plasticity: first, it provides basic neural mechanism for learning and memory, a key function of the brain; second, it provides new targets for treating brain-related disease. Long-term potentiation (LTP), mostly intensely studies in the hippocampus and amygdala, is proposed to be a cellular model for learning and memory. Although it remains difficult to understand the roles of LTP in hippocampus-related memory, a role of LTP in fear, a simplified form of memory, has been established. Here, I will review recent cellular studies of LTP in the anterior cingulate cortex (ACC) and then compare studies in vivo and in vitro LTP by genetic/ pharmacological approaches. I propose that ACC LTP may serve as a cellular model for studying central sensitization that related to chronic pain, as well as pain-related cognitive emotional disorders. Understanding signaling pathways related to ACC LTP may help us to identify novel drug target for various mental disorders.     

LTP mechanisms: from silence to four-lane traffic

Brief periods of strong neuronal activity induce long-lasting changes in synaptic function. This synaptic plasticity is thought to play important roles in learning and memory. One example--long-term potentation in the CA1 region of the hippocampus--has been studied extensively, and conflicting views regarding the underlying mechanisms have emerged. Recent findings, regarding basic properties of synaptic transmission, appear to reconcile these diverging views.     

神经元的突触可塑性与学习和记忆

大量研究表明,神经元的突触可塑性包括功能可塑性和结构可塑性,与学习和记忆密切相关.最近,在经过训练的动物海马区,记录到了学习诱导的长时程增强(long term potentiation,LTP),如果用激酶抑制剂阻断晚期LTP,就会使大鼠丧失训练形成的记忆.这些结果指出,LTP可能是形成记忆的分子基础.因此,进一步研究哺乳动物脑内突触可塑性的分子机制,对揭示学习和记忆的神经基础有重要意义.此外,在精神迟滞性疾病和神经退行性疾病患者脑内记录到异常的LTP,并发现神经元的树突棘数量减少,形态上产生畸变或萎缩,同时发现,产生突变的基因大多编码调节突触可塑性的信号通路蛋白,故突触可塑性研究也将促进精神和神经疾病的预防和治疗.综述了突触可塑性研究的最新进展,并展望了其发展前景.     

The role of mitochondrial porins and the permeability transition pore in learning and synaptic plasticity

Mitochondrial outer membrane permeability is conferred by a family of porin proteins. Mitochondrial porins conduct small molecules and constitute one component of the permeability transition pore that opens in response to apoptotic signals. Because mitochondrial porins have significant roles in diverse cellular processes including regulation of mitochondrial ATP and calcium flux, we sought to determine their importance in learning and synaptic plasticity in mice. We show that fear conditioning and spatial learning are disrupted in porin-deficient mice. Electrophysiological recordings of porin-deficient hippocampal slices reveal deficits in long and short term synaptic plasticity. Inhibition of the mitochondrial permeability transition pore by cyclosporin A in wild-type hippocampal slices reproduces the electrophysiological phenotype of porin-deficient mice. These results demonstrate a dynamic functional role for mitochondrial porins and the permeability transition pore in learning and synaptic plasticity.     

Time-dependent postsynaptic AMPA GluR1 receptor recruitment in the cingulate synaptic potentiation

The anterior cingulate cortex (ACC) is critical for brain functions including learning, memory, fear and pain. Long-term synaptic potentiation (LTP), a cellular model for learning and memory, has been reported in the ACC neurons. Unlike LTP in the hippocampus and amygdala, two key structures for memory and fear, little is known about the synaptic mechanism for the expression of LTP in the ACC. Here we use whole-cell patch clamp recordings to demonstrate that cingulate LTP requires the functional recruitment of GluR1 AMPA receptors; and such events are rapid and completed within 5-10 min after LTP induction. Our results demonstrate that the GluR1 subunit is essential for synaptic plasticity in the ACC and may play critical roles under physiological and pathological conditions.