 Your new post is loading...
Using a new, stem cell-based, drug-screening technology that could reinvent and greatly reduce the cost of developing pharmaceuticals, researchers at the Harvard Stem Cell Institute (HSCI) have found a compound that is more effective in protecting the neurons killed in amyotrophic lateral sclerosis (ALS) than are two drugs that failed in human clinical trials after large sums were invested in them. The new screening technique developed by Lee Rubin, a member of HSCI’s executive committee and a professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB), had predicted that the two drugs that eventually failed in the third and final stage of human testing would do just that. (...) - By Joseph Caputo (Harvard Staff Writer), HarvardScience, April 18, 2013
[Review] In the mammalian cortex, axons are highly ramified and link an enormous number of neurons over large distances. The conventional view assumes that action potentials (APs) are initiated at the axon initial segment in an all-or-none fashion and are then self-propagated orthodromically along axon collaterals without distortion of the AP waveform. By contrast, recent experimental results suggest that the axonal AP waveform can be modified depending on the activation states of the ion channels and receptors on axonal cell membranes. This AP modulation can regulate neurotransmission to postsynaptic neurons. In addition, the latest studies have provided evidence that cortical axons can integrate somatic burst firings and promote activity-dependent ectopic AP generation, which may underlie the oscillogenesis of fast rhythmic network activity. These seminal observations indicate that axons can perform diverse functional operations that extend beyond the prevailing model of axon physiology. (...) - by Sasaki T, Neuroscience Research, Volume 75, Issue 2, February 2013, Pages 83–88
The N-methyl-d-aspartate (NMDA) receptor plays an essential role in excitatory transmission, synaptic integration, and learning and memory. In the classical view, postsynaptic NMDA receptors act as canonical coincidence detectors providing a ‘molecular switch’ for the induction of various forms of short- and long-term synaptic plasticity. Over the past twenty years there has been accumulating evidence to suggest that NMDA receptors are also expressed presynaptically and are involved in the regulation of synaptic transmission and specific forms of activity-dependent plasticity in developing neural circuits. However, the existence of presynaptic NMDA receptors remains a contentious issue. In this review, I will discuss the criteria required for identifying functional presynaptic receptors, novel methods for probing NMDA receptor function, and recent evidence to suggest that NMDA receptors are expressed at presynaptic sites in a target-specific manner. (...) - by Duguid IC, Brain Research Bulletin, Volume 93, April 2013, Pages 4–9
The Journal of Neuroscience has published a study led by researchers at the Max Planck Florida Institute for Neuroscience, the first and only U.S. extension of the prestigious Max Planck Society, that may hold a stunning breakthrough in the fight to treat Alzheimer's disease. The study potentially identifies a cause of Alzheimer's disease - based on a newly-discovered signaling pathway in cellular models of Alzheimer's disease - and opens the door for new treatments by successfully blocking this pathway. The Institute, which recently opened in December 2012, focuses solely on basic neuroscience research that aims to analyze, map, and decode the human brain - the most important and least understood organ in the body.(...) The MPFI research indicates that the presence of Amyloid beta triggers increased levels of a signaling protein, called centaurin-alpha1 (CentA1), that appears to cause neuronal dysfunction - a potentially groundbreaking discovery that uncovers an important intermediary step in the progression of the disease.
As part of the research, the scientists were able to identify CentA1 and measure its negative effects on neurons. Utilizing an RNA silencing technique, they turned down the cellular production of CentA1, and showed that affected neurons, exposed to Amyloid beta and exhibiting Alzheimer's related symptoms, returned to normal morphology and synaptic function, even with the continued presence of Amyloid beta. They further found that increased CentA1 activates a series of proteins, and these proteins form a signaling pathway from CentA1 to neuronal dysfunction. Thus, inhibiting other proteins in the pathway also "cured" affected neurons. (...) - Medical News Today, 21 March, 2013
Synaptic mechanisms underlying memory reconsolidation after retrieval are largely unknown. Here we report that synapses in projections to the lateral nucleus of the amygdala implicated in auditory fear conditioning, which are potentiated by learning, enter a labile state after memory reactivation, and must be restabilized through a postsynaptic mechanism implicating the mammalian target of rapamycin kinase-dependent signaling. Fear-conditioning–induced synaptic enhancements were primarily presynaptic in origin. Reconsolidation blockade with rapamycin, inhibiting mammalian target of rapamycin kinase activity, suppressed synaptic potentiation in slices from fear-conditioned rats. Surprisingly, this reduction of synaptic efficacy was mediated by post- but not presynaptic mechanisms. These findings suggest that different plasticity rules may apply to the processes underlying the acquisition of original fear memory and postreactivational stabilization of fear-conditioning–induced synaptic enhancements mediating fear memory reconsolidation. - by Li Y. et al., PNAS, vol. 110 no. 12, 4798–4803
[Abstract] Current drugs for treating schizophrenia are mostly variations on a theme that was started over 50 years ago. Sadly, clinical efficacy has not improved substantially over the years. We argue that both clinical and preclinical researchers have focused too much on psychosis, which is only one of the hallmarks of schizophrenia. This narrow focus has hampered the development of relevant animal models and human experimental medicine paradigms. Other fields in psychiatry, most notably in the realms of addiction and anxiety, have prospered from results obtained in parallel studies using animal models and experimental human studies. Lessons to be learned from those models and recent genetic and cognitive insights in schizophrenia can be utilized to develop better animal and human models and, potentially, novel treatment strategies. - by Geyer MA et al., Trends in Pharmacological Sciences, Volume 33, Issue 10, 515-521, 17 July 2012
Highlights: - hERG's L622-K638 segment comprising the selectivity filter is unstructured in water.
- This segment has the potential to perturb the lipid membrane.
- Its membrane affinity is affected by K+ ions and drugs.
- It is a potential target for promethazine in the ALQTS mechanism.
- Non-specific drug–membrane interactions could play a role in the ALQTS.
(...) - by Gravel AE et al., Biochimica et Biophysica Acta (BBA) - Biomembranes, Available online 5 March 2013, In Press, Uncorrected Proof
NMDA receptor (NMDAR) activation controls long-term potentiation (LTP) as well as long-term depression (LTD) of synaptic transmission, cellular models of learning and memory. A long-standing view proposes that a high level of Ca2+ entry through NMDARs triggers LTP; lower Ca2+ entry triggers LTD. Here we show that ligand binding to NMDARs is sufficient to induce LTD; neither ion flow through NMDARs nor Ca2+ rise is required. However, basal levels of Ca2+ are permissively required. Lowering, but not maintaining, basal Ca2+levels with Ca2+ chelators blocks LTD and drives strong synaptic potentiation, indicating that basal Ca2+levels control NMDAR-dependent LTD and basal synaptic transmission. Our findings indicate that metabotropic actions of NMDARs can weaken active synapses without raising postsynaptic calcium, thereby revising and expanding the mechanisms controlling synaptic plasticity. (...) - by Nabavi S. et al., PNAS 2013 110 (10) 4027-4032
The mechanisms by which β-amyloid (Aβ), a peptide fragment believed to contribute to Alzheimer’s disease, leads to synaptic deficits are not known. Here we find that elevated oligomeric Aβ requires ion flux-independent function of NMDA receptors (NMDARs) to produce synaptic depression. Aβ activates this metabotropic NMDAR function on GluN2B-containing NMDARs but not on those containing GluN2A. Furthermore, oligomeric Aβ leads to a selective loss of synaptic GluN2B responses, effecting a switch in subunit composition from GluN2B to GluN2A, a process normally observed during development. Our results suggest that conformational changes of the NMDAR, and not ion flow through its channel, are required for Aβ to produce synaptic depression and a switch in NMDAR composition. This Aβ-induced signaling mediated by alterations in GluN2B conformation may be a target for therapeutic intervention of Alzheimer’s disease. (...) - by Kessels HW et al., PNAS, March 5, 2013 vol. 110 no. 104033-4038
A brain-to-brain interface (BTBI) enabled a real-time transfer of behaviorally meaningful sensorimotor information between the brains of two rats. In this BTBI, an “encoder” rat performed sensorimotor tasks that required it to select from two choices of tactile or visual stimuli. While the encoder rat performed the task, samples of its cortical activity were transmitted to matching cortical areas of a “decoder” rat using intracortical microstimulation (ICMS). The decoder rat learned to make similar behavioral selections, guided solely by the information provided by the encoder rat's brain. These results demonstrated that a complex system was formed by coupling the animals' brains, suggesting that BTBIs can enable dyads or networks of animal's brains to exchange, process, and store information and, hence, serve as the basis for studies of novel types of social interaction and for biological computing devices. (...) - by Pais-Vieira M. et al., Scientific Reports 3, Article number: 1319, 28 February 2013
The CDC estimated a 1% worldwide prevalence for autism spectrum disorders (ASD). In the United States, 1 out of 88 kids is diagnosed with ASD (according to data from a survey conducted in 2008). Autism spectrum disorders are characterized by diminished social interaction skills, stereotypic engagement in repetitive tasks, lengthy visual engagement with a target, refusal to deviate from set rituals and diminished spontaneity in expressing emotions. In addition to behavioral difficulties, reduced motor abilities are also reported. (...) - by Shefali Sabharanjak, PhD, Brain Blogger, February 27, 2013
Highlights - CaM was up-regulated in the hippocampus of both APP/PS1 mice and VD gerbils.
- The expression of CaV1.2 protein was increased in VD gerbils and in cultured neurons but decreased in APP/PS1 mice.
- The number of CaMKII and CaV1.2 co-localization positive neurons was decreased in AD and VD models.
(...) - by Min D et al., Neuroscience Letters, In Press, Corrected Proof, Available online 8 February 2013
Genetic mutations causing dysfunction of both voltage- and ligand-gated ion channels make a major contribution to the cause of many different types of familial epilepsy. Key mechanisms comprise defective Na+ channels of inhibitory neurons, or GABAA receptors affecting pre- or postsynaptic GABAergic inhibition, or a dysfunction of different types of channels at axon initial segments. Many of these ion channel mutations have been modelled in mice, which has largely contributed to the understanding of where and how the ion channel defects lead to neuronal hyperexcitability. Animal models of febrile seizures or mesial temporal epilepsy have shown that dendritic K+ channels, hyperpolarization-activated cation channels and T-type Ca2+ channels play important roles in the generation of seizures. For the latter, it has been shown that suppression of their function by pharmacological mechanisms or in knock-out mice can antagonize epileptogenesis. Defects of ion channel function are also associated with forms of acquired epilepsy. Autoantibodies directed against ion channels or associated proteins, such as K+ channels, LGI1 or NMDA receptors, have been identified in epileptic disorders that can largely be included under the term limbic encephalitis which includes limbic seizures, status epilepticus and psychiatric symptoms. We conclude that ion channels and associated proteins are important players in different types of genetic and acquired epilepsies. Nevertheless, the molecular bases for most common forms of epilepsy are not yet clear, and evidence to be discussed indicates just how much more we need to understand about the complex mechanisms that underlie epileptogenesis. - Lerche H et al., The Journal of Physiology, 591, 753-764., February 15, 2013
|
[Review] Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one adenosine receptor-specific agent — the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.(...) - by Chen JF et al., Nature Reviews Drug Discovery, 12, 265-286 (April 2013)
Voltage-gated ion channels are important determinants of cellular excitability. The Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) and KV7 (M-) channels are voltage-gated ion channels. Both channels are activated at sub-threshold potentials and have biophysical properties that mirror each other. KV7 channels inhibit neuronal excitability. Thus, mutations in KV7 channels that are associated with Benign Familial Neonatal Convulsions (BFNC) are likely to be epileptogenic. Mutations in HCN channels have also been associated with idiopathic epilepsies such as GEFS+. In addition, HCN channel expression and function are modulated during symptomatic epilepsies such as temporal lobe epilepsy. It is, though, unclear as to whether the changes in HCN channel expression and function associated with the various forms of epilepsy promote epileptogenesis or are adaptive. In this review, we discuss this as well as the potential for KV7 and HCN channels as drug targets for the treatment of epilepsy. (...) - by Shah MM et al., Neuropharmacology, Volume 69, June 2013, Pages 75–81
Controlling the number of AMPA receptors at synapses is fundamental for fast synaptic transmission as well as for long term adaptations in synaptic strength. In this review, we examine the biophysical mechanisms implicated in regulating AMPAR levels at the cell surface and at synapses. We first describe the structure and function of AMPARs, as well as their interactions with various proteins regulating their traffic and function. Second we review the vesicular trafficking mechanism involving exocytosis and endocytosis, by which AMPARs reach the cell surface and are internalized, respectively. Third, we examine the properties of lateral diffusion of AMPARs and their trapping at post-synaptic densities. Finally, we discuss how these two parallel mechanisms are integrated in time and space to control changes in synaptic AMPAR levels in response to plasticity protocols. This review highlights the important role of the extra-synaptic AMPAR pool, which makes an obligatory link between vesicular trafficking and trapping or release at synapses. - By Czondor k & Thoumine O, Brain Research BulletinVolume 93, April 2013, Pages 57–68
Scientists at UC San Francisco have discovered how memory recall is linked to decision-making in rats, showing that measurable activity in one part of the brain occurs when rats in a maze are playing out memories that help them decide which way to turn. The more they play out these memories, the more likely they are to find their way correctly to the end of the maze. (...) - by UCSF, ScienceBlog
[Videos] Read Montague is interested in the human dopamine system -- or, as he puts it in this illuminating talk from TEDGlobal 2012, that which makes us "chase sex, food and salt" and therefore survive. (...) - by Kate Torgovnick, TED blog, September 24, 2012
In a perspective article published in the journal Nature Neuroscience on Feb. 25, 2013, biomedical engineering professor Garrett Stanley detailed research progress toward "reading and writing the neural code." This encompasses the ability to observe the spiking activity of neurons in response to outside stimuli and make clear predictions about what is being seen, heard, or felt, and the ability to artificially introduce activity within the brain that enables someone to see, hear, or feel something that is not experienced naturally through sensory organs.(...) - Science Dailay, March 12, 2013tti
The rapidly activating, voltage gated Na+ current, INa, has recently been measured in mammalian nonmyelinated axons. Those results have been incorporated in simulations of the action potential, results that demonstrate a significant separation in time during the spike between INa and the repolarizing K+ current,IK. The original Hodgkin and Huxley (1952) model of Na+ channel gating, m3h, where m and h are channel activation and inactivation, respectively, has been used in this analysis. This model was originally developed for invertebrate nonmyelinated axons, squid giant axons in particular. The model has not survived challenges based on results from invertebrate preparations using a double-step voltage clamp protocol and measurements of gating currents, results that demonstrate a kinetic link between activation and inactivation leading to a delayed onset of inactivation following a voltage step. These processes are independent of each other in the Hodgkin and Huxley (1952) model. Application of the double-step protocol to the m3h model for mammalian INa results reveals a surprising prediction, an apparent delay in onset of inactivation even though activation and inactivation are uncoupled in the model. (...) The information obtained will be significant in determining the way in which the Na+ channel is sequestered away from its open state during repolarization, thereby allowing for a separation in time between INa and IK during a spike, an energetically efficient mechanism of neuronal signaling in the mammalian brain. (...) by John R. Clay, Progress in Biophysics and Molecular Biology, Volume 111, Issue 1, January 2013, Pages 1–7
Our eyes may be our window to the world, but how do we make sense of the thousands of images that flood our retinas each day? Scientists at the University of California, Berkeley, have found that the brain is wired to put in order all the categories of objects and actions that we see. They have created the first interactive map of how the brain organizes these groupings. (...) - By Yasmin Anwar, Media Relations UC Berkeley News Center, December 19, 2012
Highlights - A better understanding of the role of chemokines and their receptors in the CNS in addition to the immune system.
- This review focuses on recent data about three couples CXCL12/CXCR4, CCL2/CCR2, and CX3CL1/CX3CR1 in the adult CNS.
- Description of their cellular expression, distributions, and roles in neurotransmission and neuromodulation.
- This review summarizes current evidence on the role of these chemokine systems in the pathogenesis of CNS disorders.
by Réaux-Le Goazigo A. et al., Progress in Neurobiology, In Press, Available online 27 February 2013
Agonists of seven-transmembrane receptors, also known as G protein-coupled receptors (GPCRs), do not uniformly activate all cellular signalling pathways linked to a given seven-transmembrane receptor (a phenomenon termed ligand or agonist bias); this discovery has changed how high-throughput screens are designed and how lead compounds are optimized for therapeutic activity. The ability to experimentally detect ligand bias has necessitated the development of methods for quantifying agonist bias in a way that can be used to guide structure–activity studies and the selection of drug candidates. Here, we provide a viewpoint on which methods are appropriate for quantifying bias, based on knowledge of how cellular and intracellular signalling proteins control the conformation of seven-transmembrane receptors. We also discuss possible predictions of how biased molecules may perform in vivo, and what potential therapeutic advantages they may provide. (...) - by Kenakin T. & Christopoulos A., Nature Reviews Drug Discovery 12, 205-216 (March 2013)
A team of researchers from Université Laval, CHU de Québec, and pharmaceutical firm GlaxoSmithKline (GSK) has discovered a way to stimulate the brain's natural defense mechanisms in people with Alzheimer's disease. This major breakthrough, details of which are presented today in an early online edition of the Proceedings of the National Academy of Sciences (PNAS), opens the door to the development of a treatment for Alzheimer's disease and a vaccine to prevent the illness. (...) - eurekalert, 15/02/2013
The Obama administration is planning a decade-long scientific effort to examine the workings of the human brain and build a comprehensive map of its activity. (...) - by John Markoff, The New York Times, February 17,2013
|
![[Review] Presynaptic NMDA receptors: Are they dendritic receptors in disguise? | Neuroscience_topics | Scoop.it](/resources/img/white.gif)
