Molecules of the mind: integrating synaptic biochemistry to understand brain function

2006 ◽  
Vol 34 (1) ◽  
pp. 43-44
Author(s):  
L.M. Holden-Dye ◽  
V.M. O'Connor ◽  
F.A. Stephenson
Keyword(s):  
Brain Function ◽  
Transmitter Release ◽  
Receptor Activation ◽  
Experimental Models ◽  
Synaptic Function ◽  
Cellular Systems ◽  
Biochemical Basis ◽  
Molecular Determinants ◽  
The Mind ◽  
Transmitter Uptake

The focused meeting entitled ‘Molecular Determinants of Synaptic Function: Molecules and Models’ brought together several molecules and experimental models that are furthering our understanding of the biochemical basis of integrative brain function. Invited speakers and short communications from more junior scientists highlighted how individual molecules or protein networks underlie defined subcellular functions (e.g. transmitter release, receptor activation and transmitter uptake) can be used to unravel integrative function at cellular, systems and behavioural levels.

scholarly journals Sleep-wake cycles drive daily dynamics of synaptic phosphorylation

Science ◽  
2019 ◽  
Vol 366 (6462) ◽  
pp. eaav3617 ◽  
Author(s):  
Franziska Brüning ◽  
Sara B. Noya ◽  
Tanja Bange ◽  
Stella Koutsouli ◽  
Jan D. Rudolph ◽  
...  
Keyword(s):  
Brain Function ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Regulation Of Transcription ◽  
Protein Abundance ◽  
Cellular Processes ◽  
Cytoskeleton Reorganization ◽  
And Function ◽  
Daily Changes ◽  
Rest Activity

The circadian clock drives daily changes of physiology, including sleep-wake cycles, through regulation of transcription, protein abundance, and function. Circadian phosphorylation controls cellular processes in peripheral organs, but little is known about its role in brain function and synaptic activity. We applied advanced quantitative phosphoproteomics to mouse forebrain synaptoneurosomes isolated across 24 hours, accurately quantifying almost 8000 phosphopeptides. Half of the synaptic phosphoproteins, including numerous kinases, had large-amplitude rhythms peaking at rest-activity and activity-rest transitions. Bioinformatic analyses revealed global temporal control of synaptic function through phosphorylation, including synaptic transmission, cytoskeleton reorganization, and excitatory/inhibitory balance. Sleep deprivation abolished 98% of all phosphorylation cycles in synaptoneurosomes, indicating that sleep-wake cycles rather than circadian signals are main drivers of synaptic phosphorylation, responding to both sleep and wake pressures.

scholarly journals Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer

2020 ◽  
Vol 217 (6) ◽  
Author(s):  
Ivana Hermanova ◽  
Patricia Zúñiga-García ◽  
Alfredo Caro-Maldonado ◽  
Sonia Fernandez-Ruiz ◽  
Fernando Salvador ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Genetic Manipulation ◽  
Gene Dosage ◽  
Residual Activity ◽  
Low Frequency ◽  
Experimental Models ◽  
Cellular Systems ◽  
Prostate Tumorigenesis ◽  
Cancer Pathogenesis

Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination.

Introduction

2018 ◽  
Author(s):  
Jack M. Gorman
Keyword(s):  
World War Ii ◽  
Brain Function ◽  
Psychiatric Illness ◽  
Life Experiences ◽  
Human Mind ◽  
World War ◽  
Psychiatric Illnesses ◽  
The Past ◽  
Neuroscience Research ◽  
The Mind

After World War II, mental health turned toward psychopharmacology, the use of medications to treat psychiatric illnesses, as its mainstay. The success of medications led some to insist that all mental illness is due to the inheritance of abnormal genes and that life’s experiences play a diminished role. This alienated many who believe that psychotherapy is also an effective way of treating these disorders and led to a mistrust of neuroscience research. Some insisted that neuroscience ignores the human “mind.” In fact, neuroscience research in the past 50 years has clearly shown that adverse life experiences have profound effects on brain function and are involved in every psychiatric illness. By accepting this view of neuroscience, we can also accept the idea that the “mind” is in reality the work of the physical brain.

Synaptopathy: dysfunction of synaptic function?

2010 ◽  
Vol 38 (2) ◽  
pp. 443-444 ◽  
Author(s):  
Nils Brose ◽  
Vincent O'Connor ◽  
Paul Skehel
Keyword(s):  
Animal Experimentation ◽  
Structure And Function ◽  
Synaptic Function ◽  
Cellular Systems ◽  
Brain Diseases ◽  
Psychiatric Disease ◽  
Synaptic Dysfunction ◽  
A Value ◽  
Synaptic Structure ◽  
And Function

Synaptopathy is an increasingly popular term used to define key features of neurodegenerative and psychiatric disease. It implies that disruptions in synaptic structure and function are potentially the major determinant of such brain diseases. The Synaptopathies: Dysfunction of Synaptic Function Biochemical Society Focused Meeting brought together several invited speakers, supplemented with short communications from young scientists, who addressed this possibility. The talks spanned the full gamut of approaches that brought molecular, cellular, systems and whole-animal experimentation together to address how fundamental synaptic biology was increasingly informing on dysfunction in disease. The disease and models thereof discussed included Alzheimer's disease, prions, Huntington's disease, Parkinson's disease, schizophrenia and autism. The audience were asked to reflect on whether synaptopathy, although attractive and conceptually useful, provided a significant explanation as the cause of these major diseases. The breadth of the meeting reinforced the complexity of these brain diseases, supported the significance of synaptic dysfunction in disease, but left open the issue as to whether the prime cause of these disorders could be resolved as simple synaptic dysfunction. Thus, despite revealing a value of synaptopathy, further investigation will be required to reveal its balance in the cause and effect in each of the major brain diseases.

scholarly journals In Vivo Models Used for Evaluation of Potential Antigastroduodenal Ulcer Agents

Ulcers ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Michael Buenor Adinortey ◽  
Charles Ansah ◽  
Isaac Galyuon ◽  
Alexander Nyarko
Keyword(s):  
Peptic Ulcer ◽  
Animal Models ◽  
Gastrointestinal Diseases ◽  
Experimental Models ◽  
Lower Side ◽  
In Vivo Models ◽  
Biochemical Basis ◽  
Lead Compounds ◽  
Antiulcer Drugs

Peptic ulcer is among the most serious gastrointestinal diseases in the world. Several orthodox drugs are employed for the treatment of the disease. Although these drugs are effective, they produce many adverse effects thus limiting their use. In recent years, there has been a growing interest in alternative therapies, especially those from plants due to their perceived relative lower side effects, ease of accessibility, and affordability. Plant medicines with ethnomedicinal use in peptic ulcer management need to be screened for their effectiveness and possible isolation of lead compounds. This requires use of appropriate animal models of various ulcers. The limited number of antiulcer models for drug development against gastric and duodenal ulcer studies has hindered the progress of targeted therapy in this field. It is, therefore, necessary to review the literature on experimental models used to screen agents with potential antigastroduodenal ulcer activity and explain their biochemical basis in order to facilitate their use in the development of new preventive and curative antiulcer drugs. Clinical trials can then be carried out on agents/drugs that show promise. In this paper, current in vivo animal models of ulcers and the pathophysiological mechanisms underlying their induction, their limitations, as well as the challenges associated with their use have been discussed.

scholarly journals 5-HT4 receptor activation facilitates recovery from synaptic rundown and increases transmitter release from single varicosities of myenteric neurons

2008 ◽  
Vol 294 (6) ◽  
pp. G1376-G1383 ◽  
Author(s):  
Jianhua Ren ◽  
Xiaoping Zhou ◽  
James J. Galligan
Keyword(s):  
Time Constant ◽  
Transmitter Release ◽  
Acetylcholine Release ◽  
Receptor Activation ◽  
Myenteric Neurons ◽  
Receptor Agonists ◽  
Pka Pathway ◽  
Cyclase Activator ◽  
Adenylate Cyclase Activator

5-HT4 receptor agonists facilitate synaptic transmission in the enteric nervous system, and these drugs are used to treat constipation. In the present study, we investigated the effects of the 5-HT4 receptor agonist, renzapride, on rundown and recovery of fast excitatory postsynaptic potentials (fEPSPs) during and after trains of stimulation and on transmitter release from individual myenteric neuronal varicosities. Intracellular electrophysiological methods were used to record fEPSPs from neurons in longitudinal muscle myenteric plexus preparations of guinea pig ileum in vitro. During trains of supramaximal electrical stimulation (10 Hz, 2 s), fEPSP amplitude declined (time constant = 0.6 ± 0.1 s) from 17 ± 2 mV to 0.7 ± 0.3 mV. Renzapride (0.1 μM) did not change the time constant for fEPSP rundown, but it decreased the time constant for recovery of fEPSP amplitude after the stimulus train from 7 ± 2 s to 1.6 ± 0.2 s ( P < 0.05). 5-HT (0.1 μM) also increased fEPSPs and facilitated recovery from rundown. The adenylate cyclase activator, forskolin (1 μM), mimicked the actions of renzapride and 5-HT, whereas H-89, a protein kinase A (PKA) inhibitor, blocked the effects of renzapride. We used nicotinic acetylcholine receptor containing outside-out patches obtained from myenteric neurons maintained in primary culture to detect acetylcholine release from single varicosities. Renzapride (0.1 μM) increased release probability twofold. We conclude that 5-HT4 receptors activate the adenylyl cyclase-PKA pathway to increase acetylcholine release from single varicosities and to accelerate recovery from synaptic rundown. These responses may contribute to the prokinetic actions of 5-HT4 receptor agonists.

PTH(1–84)/PTH(7–84): a balance of power

2006 ◽  
Vol 290 (5) ◽  
pp. F975-F984 ◽  
Author(s):  
Peter A. Friedman ◽  
William G. Goodman
Keyword(s):  
Renal Failure ◽  
Parathyroid Hormone ◽  
Bone Histomorphometry ◽  
Bone Biopsy ◽  
Balance Of Power ◽  
Receptor Activation ◽  
Experimental Models ◽  
Failure Diagnosis ◽  
Clinical Aspects ◽  
The Relationship

This review considers many new basic and clinical aspects of parathyroid hormone (PTH). We focus especially on the identification of PTH fragments and how they may relate to renal failure, diagnosis, and treatment of secondary hyperparathyroidism and renal osteodystrophy. The biosynthesis and metabolism of PTH, measurement of circulating forms of PTH, the effects of PTH on receptor activation and turnover, the relationship between PTH levels and bone turnover in renal failure in humans, and the involvement of PTH in experimental models of renal failure are discussed. Despite these developments in understanding the etiology of renal failure and the availability of new assays for bioactive PTH, no adequate surrogate for bone biopsy and quantitative bone histomorphometry has been developed.

Brain, Mind and Behaviour

1993 ◽  
Vol 163 (5) ◽  
pp. 565-573 ◽  
Author(s):  
Peter Fenwick
Keyword(s):  
Brain Function ◽  
Imaging Techniques ◽  
Psychiatric Illnesses ◽  
The Mind ◽  
The Brain ◽  
Apparent Conflict

The advent of new imaging techniques is broadening our understanding of the major psychiatric illnesses. The increased knowledge of brain function will have consequences for the expert medical witness who has to give evidence in court. Both the insanity defence and the defence of automatism depend on disorders of the mind. Psychiatry is now able in many cases to produce evidence that these are consequent upon disorders of the brain. In presenting evidence in court there is an apparent conflict between ‘brain words' and ‘mind words'.

scholarly journals Intracellular Ca2+Stores and Ca2+Influx Are Both Required for BDNF to Rapidly Increase Quantal Vesicular Transmitter Release

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Michelle D. Amaral ◽  
Lucas Pozzo-Miller
Keyword(s):  
Transmitter Release ◽  
Time Course ◽  
Pyramidal Neurons ◽  
Receptor Activation ◽  
Trpc Channels ◽  
Styryl Dyes ◽  
Trkb Receptors ◽  
Mepsc Frequency ◽  
Intracellular Ca

Brain-derived neurotrophic factor (BDNF) is well known as a survival factor during brain development as well as a regulator of adult synaptic plasticity. One potential mechanism to initiate BDNF actions is through its modulation of quantal presynaptic transmitter release. In response to local BDNF application to CA1 pyramidal neurons, the frequency of miniature excitatory postsynaptic currents (mEPSC) increased significantly within 30 seconds; mEPSC amplitude and kinetics were unchanged. This effect was mediated via TrkB receptor activation and required both full intracellular Ca2+stores as well as extracellular Ca2+. Consistent with a role of Ca2+-permeable plasma membrane channels of the TRPC family, the inhibitor SKF96365 prevented the BDNF-induced increase in mEPSC frequency. Furthermore, labeling presynaptic terminals with amphipathic styryl dyes and then monitoring their post-BDNF destaining in slice cultures by multiphoton excitation microscopy revealed that the increase in frequency of mEPSCs reflects vesicular fusion events. Indeed, BDNF application to CA3-CA1 synapses in TTX rapidly enhanced FM1-43 or FM2-10 destaining with a time course that paralleled the phase of increased mEPSC frequency. We conclude that BDNF increases mEPSC frequency by boosting vesicular fusion through a presynaptic, Ca2+-dependent mechanism involving TrkB receptors, Ca2+stores, and TRPC channels.

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