http://www.molecularbrain.com The latest research articles published by Molecular Brain 2012-05-14T00:00:00Z 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 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 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 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 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 Background: A loss of function of the L-type calcium channel, Cav1.2, results in a cardiac specific disease known as Brugada syndrome. Although many Brugada syndrome channelopathies reduce channel function, one point mutation in the N-terminus of Cav1.2 (A39V) has been shown to elicit disease a phenotype because of a loss of surface trafficking of the channel. This lack of cell membrane expression could not be rescued by the trafficking chaperone Cavβ.FindingsWe report that despite the striking loss of trafficking described previously in the cardiac Cav1.2 channel, the A39V mutation while in the background of the brain isoform traffics and functions normally. We detected no differences in biophysical properties between wild type Cav1.2 and A39V-Cav1.2 in the presence of either a cardiac (Cavβ2b), or a neuronal beta subunit (Cavβ1b). In addition, the A39V-Cav1.2 mutant showed a normal Cavβ2b mediated increase in surface expression in tsA-201 cells. Conclusions: The Brugada syndrome mutation A39V when introduced into rat brain Cav1.2 does not trigger the loss-of-trafficking phenotype seen in a previous study on the human heart isoform of the channel. http://www.molecularbrain.com/content/5/1/9 Brett Simms Gerald Zamponi Molecular Brain 2012, null:9 2012-03-02T00:00:00Z doi:10.1186/1756-6606-5-9 /content/figures/1756-6606-5-9-toc.gif Molecular Brain 1756-6606 ${item.volume} 9 2012-03-02T00:00:00Z XML Background: Retinoid signaling pathways mediated by retinoic acid receptor (RAR)/retinoid × receptor (RXR)-mediated transcription play critical roles in hippocampal synaptic plasticity. Furthermore, recent studies have shown that treatment with retinoic acid alleviates age-related deficits in hippocampal long-term potentiation (LTP) and memory performance and, furthermore, memory deficits in a transgenic mouse model of Alzheimer's disease. However, the roles of the RAR/RXR signaling pathway in learning and memory at the behavioral level have still not been well characterized in the adult brain. We here show essential roles for RAR/RXR in hippocampus-dependent learning and memory. In the current study, we generated transgenic mice in which the expression of dominant-negative RAR (dnRAR) could be induced in the mature brain using a tetracycline-dependent transcription factor and examined the effects of RAR/RXR loss. Results: The expression of dnRAR in the forebrain down-regulated the expression of RARβ, a target gene of RAR/RXR, indicating that dnRAR mice exhibit dysfunction of the RAR/RXR signaling pathway. Similar with previous findings, dnRAR mice displayed impaired LTP and AMPA-mediated synaptic transmission in the hippocampus. More importantly, these mutant mice displayed impaired hippocampus-dependent social recognition and spatial memory. However, these deficits of LTP and memory performance were rescued by stronger conditioning stimulation and spaced training, respectively. Finally, we found that pharmacological blockade of RARα in the hippocampus impairs social recognition memory. Conclusions: From these observations, we concluded that the RAR/RXR signaling pathway greatly contributes to learning and memory, and LTP in the hippocampus in the adult brain. http://www.molecularbrain.com/content/5/1/8 Masanori Nomoto Yohei Takeda Shusaku Uchida Koji Mitsuda Hatsune Enomoto Kaori Saito Tesu Choi Ayako Watabe Shizuka Kobayashi Shoichi Masushige Toshiya Manabe Satoshi Kida Molecular Brain 2012, null:8 2012-02-08T00:00:00Z doi:10.1186/1756-6606-5-8 /content/figures/1756-6606-5-8-toc.gif Molecular Brain 1756-6606 ${item.volume} 8 2012-02-08T00:00:00Z XML Background: The neuromuscular junction (NMJ) is a cholinergic synapse that rapidly conveys signals from motoneurons to muscle cells and exhibits a high degree of subcellular specialization characteristic of chemical synapses. NMJ formation requires agrin and its coreceptors LRP4 and MuSK. Increasing evidence indicates that Wnt signaling regulates NMJ formation in Drosophila, C. elegans and zebrafish. Results: In the study we systematically studied the effect of all 19 different Wnts in mammals on acetylcholine receptor (AChR) cluster formation. We identified five Wnts (Wnt9a, Wnt9b, Wnt10b, Wnt11, and Wnt16) that are able to stimulate AChR clustering, of which Wnt9a and Wnt11 are expressed abundantly in developing muscles. Using Wnt9a and Wnt11 as example, we demonstrated that Wnt induction of AChR clusters was dose-dependent and non-additive to that of agrin, suggesting that Wnts may act via similar pathways to induce AChR clusters. We provide evidence that Wnt9a and Wnt11 bind directly to the extracellular domain of MuSK, to induce MuSK dimerization and subsequent tyrosine phosphorylation of the kinase. In addition, Wnt-induced AChR clustering requires LRP4. Conclusions: These results identify Wnts as new players in AChR cluster formation, which act in a manner that requires both MuSK and LRP4, revealing a novel function of LRP4. http://www.molecularbrain.com/content/5/1/7 Bin Zhang Chuan Liang Ryan Bates Yimin Yin Wen-Cheng Xiong Lin Mei Molecular Brain 2012, null:7 2012-02-06T00:00:00Z doi:10.1186/1756-6606-5-7 /content/figures/1756-6606-5-7-toc.gif Molecular Brain 1756-6606 ${item.volume} 7 2012-02-06T00:00:00Z XML Although the cortex has been extensively studied in long-term memory storage, less emphasis has been placed on immediate cortical contributions to fear memory formation. AMPA receptor plasticity is strongly implicated in learning and memory, and studies have identified calcium permeable AMPA receptors (CP-AMPARs) as mediators of synaptic strengthening. Trace fear learning engages the anterior cingulate cortex (ACC), but whether plastic events occur within the ACC in response to trace fear learning, and whether GluN2B subunits are required remains unknown. Here we show that the ACC is necessary for trace fear learning, and shows a rapid 20% upregulation of membrane AMPA receptor GluA1 subunits that is evident immediately after conditioning. Inhibition of NMDA receptor GluN2B subunits during training prevented the upregulation, and disrupted trace fear memory retrieval 48 h later. Furthermore, intra-ACC injections of the CP-AMPAR channel antagonist, 1-naphthylacetyl spermine (NASPM) immediately following trace fear conditioning blocked 24 h fear memory retrieval. Accordingly, whole cell patch clamp recordings from c-fos positive and c-fos negative neurons within the ACC in response to trace fear learning revealed an increased sensitivity to NASPM in recently activated neurons that was reversed by reconsolidation update extinction. Our results suggest that trace fear learning is mediated through rapid GluN2B dependent trafficking of CP-AMPARs, and present in vivo evidence that CP-AMPAR activity within the ACC immediately after conditioning is necessary for subsequent memory consolidation processes. http://www.molecularbrain.com/content/5/1/6 Giannina Descalzi Xiang-Yao Li Tao Chen Valentina Mercaldo Kohei Koga Min Zhuo Molecular Brain 2012, null:6 2012-02-03T00:00:00Z doi:10.1186/1756-6606-5-6 /content/figures/1756-6606-5-6-toc.gif Molecular Brain 1756-6606 ${item.volume} 6 2012-02-03T00:00:00Z XML