http://www.molecularbrain.com The most accessed research articles published by Molecular Brain 2012-05-14T00:00:00Z The analysis of the contributions to synaptic plasticity and memory of cAMP, PKA, CRE,CREB-1, CREB-2, and CPEB has recruited the efforts of many laboratories all over theworld. These are six key steps in the molecular biological delineation of short-term memoryand its conversion to long-term memory for both implicit (procedural) and explicit(declarative) memory. I here first trace the background for the clinical and behavioral studiesof implicit memory that made a molecular biology of memory storage possible, and thendetail the discovery and early history of these six molecular steps and their roles in explicitmemory. http://www.molecularbrain.com/content/5/1/14 Eric Kandel Molecular Brain 2012, null:14 2012-05-14T00:00:00Z doi:10.1186/1756-6606-5-14 Molecules of memory Eric Kandel gives a broad historical overview of the major molecular components of short and long-term memory. /content/figures/1756-6606-5-14-toc.gif Molecular Brain 1756-6606 ${item.volume} 14 2012-05-14T00:00:00Z PDF Over-activation of AMPARs (alphaamino-3-hydroxy-5-methylisoxazole-4-propionic acidsubtype glutamate receptors) is implicated in excitotoxic neuronal death associated with acutebrain insults, such as ischemic stroke. However, the specific molecular mechanism by whichAMPARs, especially the calcium-impermeable AMPARs, induce neuronal death remainspoorly understood. Here we report the identification of a previously unrecognized molecularpathway involving a direct protein-protein interaction that underlies GluR2-containingAMPAR-mediated excitotoxicity. Agonist stimulation of AMPARs promotes GluR2/GAPDH(glyceraldehyde-3-phosphate dehydrogenase) complex formation and subsequentinternalization. Disruption of GluR2/GAPDH interaction by administration of an interferingpeptide prevents AMPAR-mediated excitotoxicity and protects against damage induced byoxygen-glucose deprivation (OGD), an in vitro model of brain ischemia. http://www.molecularbrain.com/content/5/1/13 Min Wang Shupeng Li Hongyu Zhang Lin Pei Shengwei Zou Frank Lee Yu Tian Wang Fang Liu Molecular Brain 2012, null:13 2012-04-26T00:00:00Z doi:10.1186/1756-6606-5-13 /content/figures/1756-6606-5-13-toc.gif Molecular Brain 1756-6606 ${item.volume} 13 2012-04-26T00:00:00Z PDF An important pathological feature of Alzheimer's disease (AD) is the presence of extracellular senile plaques in the brain. Senile plaques are composed of aggregations of small peptides called β-amyloid (Aβ). Multiple lines of evidence demonstrate that overproduction/aggregation of Aβ in the brain is a primary cause of AD and inhibition of Aβ generation has become a hot topic in AD research. Aβ is generated from β-amyloid precursor protein (APP) through sequential cleavages first by β-secretase and then by γ-secretase complex. Alternatively, APP can be cleaved by α-secretase within the Aβ domain to release soluble APPα and preclude Aβ generation. Cleavage of APP by caspases may also contribute to AD pathologies. Therefore, understanding the metabolism/processing of APP is crucial for AD therapeutics. Here we review current knowledge of APP processing regulation as well as the patho/physiological functions of APP and its metabolites. http://www.molecularbrain.com/content/4/1/3 Yun-wu Zhang Robert Thompson Han Zhang Huaxi Xu Molecular Brain 2011, null:3 2011-01-07T00:00:00Z doi:10.1186/1756-6606-4-3 /content/figures/1756-6606-4-3-toc.gif Molecular Brain 1756-6606 ${item.volume} 3 2011-01-07T00:00:00Z XML Background: In the central nervous system (CNS), the muscarinic system plays key roles in learning and memory, as well as in the regulation of many sensory, motor, and autonomic processes, and is thought to be involved in the pathophysiology of several major diseases of the CNS, such as Alzheimer's disease, depression, and schizophrenia. Previous studies reveal that M4 muscarinic receptor knockout (M4R KO) mice displayed an increase in basal locomotor activity, an increase in sensitivity to the prepulse inhibition (PPI)-disrupting effect of psychotomimetics, and normal basal PPI. However, other behaviorally significant roles of M4R remain unclear. Results: In this study, to further investigate precise functional roles of M4R in the CNS, M4R KO mice were subjected to a battery of behavioral tests. M4R KO mice showed no significant impairments in nociception, neuromuscular strength, or motor coordination/learning. In open field, light/dark transition, and social interaction tests, consistent with previous studies, M4R KO mice displayed enhanced locomotor activity compared to their wild-type littermates. In the open field test, M4R KO mice exhibited novelty-induced locomotor hyperactivity. In the social interaction test, contacts between pairs of M4R KO mice lasted shorter than those of wild-type mice. In the sensorimotor gating test, M4R KO mice showed a decrease in PPI, whereas in the startle response test, in contrast to a previous study, M4R KO mice demonstrated normal startle response. M4R KO mice also displayed normal performance in the Morris water maze test. Conclusions: These findings indicate that M4R is involved in regulation of locomotor activity, social behavior, and sensorimotor gating in mice. Together with decreased PPI, abnormal social behavior, which was newly identified in the present study, may represent a behavioral abnormality related to psychiatric disorders including schizophrenia. http://www.molecularbrain.com/content/5/1/10 Hisatsugu Koshimizu Lorene Leiter Tsuyoshi Miyakawa Molecular Brain 2012, null:10 2012-04-02T00:00:00Z doi:10.1186/1756-6606-5-10 /content/figures/1756-6606-5-10-toc.gif Molecular Brain 1756-6606 ${item.volume} 10 2012-04-02T00:00:00Z PDF Neuropathic pain is generally defined as a chronic pain state resulting from peripheral and/or central nerve injury. Effective treatment for neuropathic pain is still lacking, due in part to poor understanding of pathological mechanisms at the molecular level. Neuronal mechanisms of neuropathic pain, especially synaptic plasticity, are the major focus of many investigators. N-methyl-D-aspartate (NMDA) receptor dependent synaptic plasticity at the spinal and cortical levels is believed to contribute to enhanced sensory responses after injury. Glial cells, including astrocytes and microglia, have recently been implicated in neuropathic pain. These glial cells form close interactions with neurons and thus may modulate nociceptive transmission under pathological conditions. In this review, we present recent progress in the study of neuronal and microglial mechanisms underlying neuropathic pain. We propose that activity-dependent neuronal plasticity is a key target for treatment in neuropathic pain. http://www.molecularbrain.com/content/4/1/31 Min Zhuo Gongxiong Wu Long-Jun Wu Molecular Brain 2011, null:31 2011-07-30T00:00:00Z doi:10.1186/1756-6606-4-31 /content/figures/1756-6606-4-31-toc.gif Molecular Brain 1756-6606 ${item.volume} 31 2011-07-30T00:00:00Z XML Background: Glutathione (GSH) plays an important role in neuronal oxidant defence. Depletion of cellular GSH is observed in neurodegenerative diseases and thereby contributes to the associated oxidative stress and Ca2+ dysregulation. Whether depletion of cellular GSH, associated with neuronal senescence, directly influences Ca2+ permeation pathways is not known. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+ permeable non-selective cation channel expressed in several cell types including hippocampal pyramidal neurons. Moreover, activation of TRPM2 during oxidative stress has been linked to cell death. Importantly, GSH has been reported to inhibit TRPM2 channels, suggesting they may directly contribute to Ca2+ dysregulation associated with neuronal senescence. Herein, we explore the relation between cellular GSH and TRPM2 channel activity in long-term cultures of hippocampal neurons. Results: In whole-cell voltage-clamp recordings, we observe that TRPM2 current density increases in cultured pyramidal neurons over time in vitro. The observed increase in current density was prevented by treatment with NAC, a precursor to GSH synthesis. Conversely, treatment of cultures maintained for 2 weeks in vitro with L-BSO, which depletes GSH by inhibiting its synthesis, augments TRPM2 currents. Additionally, we demonstrate that GSH inhibits TRPM2 currents through a thiol-independent mechanism, and produces a 3.5-fold shift in the dose-response curve generated by ADPR, the intracellular agonist for TRPM2. Conclusion: These results indicate that GSH plays a physiologically relevant role in the regulation of TRPM2 currents in hippocampal pyramidal neurons. This interaction may play an important role in aging and neurological diseases associated with depletion of GSH. http://www.molecularbrain.com/content/5/1/11 Jillian Belrose Yu-Feng Xie Lynn Gierszewski John MacDonald Michael Jackson Molecular Brain 2012, null:11 2012-04-09T00:00:00Z doi:10.1186/1756-6606-5-11 /content/figures/1756-6606-5-11-toc.gif Molecular Brain 1756-6606 ${item.volume} 11 2012-04-09T00:00:00Z XML Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders. http://www.molecularbrain.com/content/1/1/6 Nobuyuki Yamasaki Motoko Maekawa Katsunori Kobayashi Yasushi Kajii Jun Maeda Miho Soma Keizo Takao Koichi Tanda Koji Ohira Keiko Toyama Kouji Kanzaki Kohji Fukunaga Yusuke Sudo Hiroshi Ichinose Masashi Ikeda Nakao Iwata Norio Ozaki Hidenori Suzuki Makoto Higuchi Tetsuya Suhara Shigeki Yuasa Tsuyoshi Miyakawa Molecular Brain 2008, null:6 2008-09-10T00:00:00Z doi:10.1186/1756-6606-1-6 /content/figures/1756-6606-1-6-toc.gif Molecular Brain 1756-6606 ${item.volume} 6 2008-09-10T00:00:00Z XML Background: Nerve cells program the brain codes to manage well-organized cognitions and behaviors. Itremains unclear how a population of neurons and astrocytes work coordinately to encodetheir spatial and temporal activity patterns in response to frequency and intensity signals fromsensory inputs. Results: With two-photon imaging and electrophysiology to record cellular functions in the barrelcortex in vivo, we analyzed the activity patterns of neurons and astrocytes in response towhisker stimuli with increasing frequency, an environmental stimulus pattern that rodentsexperience in the accelerated motion. Compared to the resting state, whisker stimulationcaused barrel neurons and astrocytes to be activated more synchronously. An increasedstimulus frequency up-regulated the activity strength of neurons and astrocytes as well ascoordinated their interaction. The coordination among the barrel neurons and astrocytes wasfulfilled by increasing their functional connections. Conclusions: Our study reveals that the nerve cells in the barrel cortex encode frequency messages inwhisker tactile inputs through setting their activity coordination. http://www.molecularbrain.com/content/5/1/12 Jun Zhao Dangui Wang Jin-Hui Wang Molecular Brain 2012, null:12 2012-04-26T00:00:00Z doi:10.1186/1756-6606-5-12 /content/figures/1756-6606-5-12-toc.gif Molecular Brain 1756-6606 ${item.volume} 12 2012-04-26T00:00:00Z PDF Caspases are a family of cysteine proteases that play key roles in programmed cell death (apoptosis). Mounting evidence in recent years shows that caspases also have important non-apoptotic functions in multiple cellular processes, such as synaptic plasticity, dendritic development, learning and memory. In this article, we review the studies on the non-apoptotic functions of caspases in neurons, with a focus on their roles in synaptic plasticity, learning and memory and neurodegeneration. http://www.molecularbrain.com/content/5/1/15 Zheng Li Morgan Sheng Molecular Brain 2012, null:15 2012-05-14T00:00:00Z doi:10.1186/1756-6606-5-15 /content/figures/1756-6606-5-15-toc.gif Molecular Brain 1756-6606 ${item.volume} 15 2012-05-14T00:00:00Z PDF Extensive studies have led to a variety of hypotheses for the molecular basis of depression and related mood disorders, but a definite pathogenic mechanism has yet to be defined. The monoamine hypothesis, in conjunction with the efficacy of antidepressants targeting monoamine systems, has long been the central topic of depression research. While it is widely embraced that the initiation of antidepressant efficacy may involve acute changes in monoamine systems, apparently, the focus of current research is moving toward molecular mechanisms that underlie long-lasting downstream changes in the brain after chronic antidepressant treatment, thereby reaching for a detailed view of the pathophysiology of depression and related mood disorders. In this minireview, we briefly summarize major themes in current approaches to understanding mood disorders focusing on molecular views of depression and antidepressant action. http://www.molecularbrain.com/content/3/1/8 Saebom Lee Jaehoon Jeong Yongdo Kwak Sang Ki Park Molecular Brain 2010, null:8 2010-03-10T00:00:00Z doi:10.1186/1756-6606-3-8 /content/figures/1756-6606-3-8-toc.gif Molecular Brain 1756-6606 ${item.volume} 8 2010-03-10T00:00:00Z XML