scholarly journals Enhancing synaptic plasticity and cellular resilience to develop novel, improved treatments for mood disorders

2002 ◽  
Vol 4 (1) ◽  
pp. 73-92
Keyword(s):  
Synaptic Plasticity ◽  
Cell Survival ◽  
Signaling Pathways ◽  
Mood Disorders ◽  
Map Kinases ◽  
Adenosine Monophosphate ◽  
Mood Stabilizers ◽  
Cellular Mechanisms ◽  
Cellular Resilience

There is mounting evidence that recurrent mood disorders - once considered "good prognosis diseases"- are, in fact, often very severe and life-threatening illnesses. Furthermore, although mood disorders have traditionally been conceptualized as neurochemical disorders, there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes ofglia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggest that mood disorders are associated with impairments of synaptic plasticity and cellular resilience. In this context, it is noteworthy that there is increasing preclinical evidence that antidepressants regulate the function of the glutamatergic system. Moreover, although clearly preliminary, the available clinical data suggest that attenuation of N-methyl-D-aspartate (NMDA) function has antidepressant effects. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressant agents. Antidepressants and mood stabilizers indirectly regulate a number of factors involved in cell survival pathways, including cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), the antiapoptotic protein bcl-2, and mitogen-activated protein (MAP) kinases, and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects. There is much promise for the future development of treatments that more directly target molecules in critical CNS signaling pathways regulating synaptic plasticity and cellular resilience. These will represent improved long-term treatments for mood disorders.

scholarly journals Bipolar disorder: involvement of signaling cascades and AMPA receptor trafficking at synapses

2004 ◽  
Vol 1 (3) ◽  
pp. 231-243 ◽  
Author(s):  
JING DU ◽  
JORGE QUIROZ ◽  
PEIXIONG YUAN ◽  
CARLOS ZARATE ◽  
HUSSEINI K. MANJI
Keyword(s):  
Synaptic Plasticity ◽  
Mood Disorders ◽  
Ampa Receptor ◽  
Glycogen Synthase ◽  
Receptor Trafficking ◽  
Mood Stabilizers ◽  
Signaling Cascades ◽  
Glutamatergic System ◽  
Ample Evidence ◽  
Cellular Resilience

There is increasing evidence that severe mood disorders are associated with impairment of structural plasticity and cellular resilience. Cumulative data demonstrate that mood stabilizers regulate intracellular signaling cascades, including protein kinase C (PKC), PKA, mitogen-activated protein (MAP) kinase, glycogen synthase kinase 3-β (GSK3-β) and intracellular calcium, which are signaling pathways that regulate synaptic plasticity. In this context, it is noteworthy that a growing body of data indicates that the glutamatergic system, has a major role in neuronal plasticity and cellular resilience, might be involved in the pathophysiology and treatment of mood disorders. AMPA glutamate-receptor trafficking is important in synaptic plasticity and might play crucial roles in maintaining critical neuronal circuits associated with mood. Two clinically effective, structurally dissimilar, antimanic agents, lithium and valproate (VPA), down-regulate synaptic expression of AMPA receptor subunit GluR1 in hippocampus in chronically treated rats. This reduction in synaptic GluR1 by lithium and VPA is due to attenuated phosphorylation of GluR1 at a specific PKA site (residue 845 of GluR1), which is crucial for AMPA receptor insertion. By contrast, imipramine, which can provoke mania, increases synaptic expression of GluR1 in the hippocampus in vivo. Furthermore, there is ample evidence from preclinical and clinical research that the glutamatergic system is involved in the pathophysiology of mood disorders and that many of the somatic treatments used for mood disorders including antidepressants, mood stabilizers, atypical antipsychotic drugs and electroconvulsive therapy have both direct and indirect effects on the glutamatergic system. Given these findings, further research with medications that specifically affect the glutamatergic system is warranted. Recent studies in our lab have shown that riluzole, a FDA approved medicine that regulates the glutamatergic system, shows antidepressant efficacy in unipolar and bipolar depression. These studies indicate that regulation of glutamate-mediated synaptic plasticity might play a role in the treatment of mood disorders, and raise new avenues for novel therapies for this devastating illness.

scholarly journals Synaptic Plasticity and its Modulation by Alcohol

2020 ◽  
Vol 6 (1) ◽  
pp. 103-111 ◽  
Author(s):  
Yosef Avchalumov ◽  
Chitra D. Mandyam
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Dorsal Striatum ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
Public Health Issue ◽  
Cellular Mechanisms ◽  
Brain Disorder ◽  
The Brain

Alcohol is one of the oldest pharmacological agents used for its sedative/hypnotic effects, and alcohol abuse and alcohol use disorder (AUD) continues to be major public health issue. AUD is strongly indicated to be a brain disorder, and the molecular and cellular mechanism/s by which alcohol produces its effects in the brain are only now beginning to be understood. In the brain, synaptic plasticity or strengthening or weakening of synapses, can be enhanced or reduced by a variety of stimulation paradigms. Synaptic plasticity is thought to be responsible for important processes involved in the cellular mechanisms of learning and memory. Long-term potentiation (LTP) is a form of synaptic plasticity, and occurs via N-methyl-D-aspartate type glutamate receptor (NMDAR or GluN) dependent and independent mechanisms. In particular, NMDARs are a major target of alcohol, and are implicated in different types of learning and memory. Therefore, understanding the effect of alcohol on synaptic plasticity and transmission mediated by glutamatergic signaling is becoming important, and this will help us understand the significant contribution of the glutamatergic system in AUD. In the first part of this review, we will briefly discuss the mechanisms underlying long term synaptic plasticity in the dorsal striatum, neocortex and the hippocampus. In the second part we will discuss how alcohol (ethanol, EtOH) can modulate long term synaptic plasticity in these three brain regions, mainly from neurophysiological and electrophysiological studies. Taken together, understanding the mechanism(s) underlying alcohol induced changes in brain function may lead to the development of more effective therapeutic agents to reduce AUDs.

scholarly journals Regulation of cellular plasticity and resilience by mood stabilizers: the role of AMPA receptor trafficking

2004 ◽  
Vol 6 (2) ◽  
pp. 143-155
Keyword(s):  
Mood Disorders ◽  
Neural Plasticity ◽  
Neuronal Plasticity ◽  
Brain Volume ◽  
Critical Role ◽  
Receptor Trafficking ◽  
Mood Stabilizers ◽  
Brain Areas ◽  
Cellular Resilience

There is increasing evidence from a variety of sources that severe mood disorders are associated with regional reductions in brain volume, as well as reductions in the number, size, and density of glia and neurons in discrete brain areas. Although the precise pathophysiology underlying these morphometric changes remains to be fully elucidated, the data suggest that severe mood disorders are associated with impairments of structural plasticity and cellular resilience. In this context, it is noteworthy that a growing body of data suggests that the glutamaiergic system (which is known to play a major role in neuronal plasticity and cellular resilience) may be involved in the pathophysiology and treatment of mood disorders. Glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) GluR1 receptor trafficking plays a critical role in regulating various forms of neural plasticity. It is thus noteworthy that recent studies have shown that structurally dissimilar mood stabilizers lithium and valproate regulate GluR1 receptor subunit trafficking and localization at synapses. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raises the possibility that agents more directly affecting synaptic GluR1 represent novel therapies for these devastating illnesses.

scholarly journals Persistent memories of long-term potentiation and the N-methyl-d-aspartate receptor

2019 ◽  
Vol 3 ◽  
pp. 239821281984821 ◽  
Author(s):  
TVP Bliss ◽  
GL Collingridge
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Brain Disorders ◽  
Molecular Pharmacology ◽  
Cellular Mechanisms ◽  
Long Term Depression ◽  
Aspartate Receptor ◽  
Term Potentiation ◽  
Core Feature

In this article, we describe our involvement in the early days of research into long-term potentiation. We start with a description of the early experiments conducted in Oslo and London where long-term potentiation was first characterised. We discuss the ways in which the molecular pharmacology of glutamate receptors control the induction and expression of long-term potentiation and its counterpart, long-term depression. We then go on to summarise the extraordinary advances in understanding the cellular mechanisms of synaptic plasticity that have taken place in the subsequent half century. Finally, the increasing evidence that impaired long-term potentiation is a core feature of many brain disorders (LToPathies) is addressed by way of a few selected examples.

Mode of action of electroconvulsive therapy: an update

2011 ◽  
Vol 17 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Allan I. F. Scott
Keyword(s):  
Mood Disorders ◽  
Electroconvulsive Therapy ◽  
Mode Of Action ◽  
Imaging Techniques ◽  
Long Term Effects ◽  
Cellular Mechanisms ◽  
Know How ◽  
Antidepressant Treatments ◽  
New Findings

SummaryIt has become acceptable for psychiatrists to say that they simply do not know how electroconvulsive therapy (ECT) works. This frame of mind runs the risk that there will be no expectation that psychiatrists remain familiar with seminal studies on the mode of action of ECT. This article is intended as a reminder of these studies and illustrates how the original theories have evolved. This evolution has been brought about largely by modern brain imaging techniques in human studies and in patients treated with ECT. These new findings will be set in the context of contemporary ideas about the neuroanatomy of mood disorders and the cellular mechanisms of the long-term effects of antidepressant treatments.

scholarly journals CAPS1 is involved in hippocampal synaptic plasticity and hippocampus-associated learning

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chiaki Ishii ◽  
Natsumi Shibano ◽  
Mio Yamazaki ◽  
Tomoki Arima ◽  
Yuna Kato ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Conditional Knockout ◽  
Cellular Mechanisms ◽  
Adeno Associated Virus ◽  
Calcium Dependent ◽  
Term Potentiation ◽  
Hippocampal Ca3 ◽  
Vesicular Exocytosis

AbstractCalcium-dependent activator protein for secretion 1 (CAPS1) is a key molecule in vesicular exocytosis, probably in the priming step. However, CAPS1’s role in synaptic plasticity and brain function is elusive. Herein, we showed that synaptic plasticity and learning behavior were impaired in forebrain and/or hippocampus-specific Caps1 conditional knockout (cKO) mice by means of molecular, physiological, and behavioral analyses. Neonatal Caps1 cKO mice showed a decrease in the number of docked vesicles in the hippocampal CA3 region, with no detectable changes in the distribution of other major exocytosis-related molecules. Additionally, long-term potentiation (LTP) was partially and severely impaired in the CA1 and CA3 regions, respectively. CA1 LTP was reinforced by repeated high-frequency stimuli, whereas CA3 LTP was completely abolished. Accordingly, hippocampus-associated learning was severely impaired in adeno-associated virus (AAV) infection-mediated postnatal Caps1 cKO mice. Collectively, our findings suggest that CAPS1 is a key protein involved in the cellular mechanisms underlying hippocampal synaptic release and plasticity, which is crucial for hippocampus-associated learning.

scholarly journals Rho Signaling in Synaptic Plasticity, Memory, and Brain Disorders

2021 ◽  
Vol 9 ◽  
Author(s):  
Haorui Zhang ◽  
Youssif Ben Zablah ◽  
Haiwang Zhang ◽  
Zhengping Jia
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Small Gtpases ◽  
Structural Basis ◽  
Brain Disorders ◽  
Rho Proteins ◽  
Cellular Mechanisms ◽  
Spine Morphology ◽  
Memory Impairments

Memory impairments are associated with many brain disorders such as autism, Alzheimer’s disease, and depression. Forming memories involves modifications of synaptic transmission and spine morphology. The Rho family small GTPases are key regulators of synaptic plasticity by affecting various downstream molecules to remodel the actin cytoskeleton. In this paper, we will review recent studies on the roles of Rho proteins in the regulation of hippocampal long-term potentiation (LTP) and long-term depression (LTD), the most extensively studied forms of synaptic plasticity widely regarded as cellular mechanisms for learning and memory. We will also discuss the involvement of Rho signaling in spine morphology, the structural basis of synaptic plasticity and memory formation. Finally, we will review the association between brain disorders and abnormalities of Rho function. It is expected that studying Rho signaling at the synapse will contribute to the understanding of how memory is formed and disrupted in diseases.

scholarly journals Syndapin I Loss-of-Function in Mice Leads to Schizophrenia-Like Symptoms

2020 ◽  
Vol 30 (8) ◽  
pp. 4306-4324 ◽  
Author(s):  
Nicole Koch ◽  
Dennis Koch ◽  
Sarah Krueger ◽  
Jessica Tröger ◽  
Victor Sabanov ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Synaptic Activity ◽  
Actin Dynamics ◽  
Loss Of Function ◽  
Cellular Mechanisms ◽  
Long Term Depression ◽  
Membrane Recruitment ◽  
Term Potentiation

Abstract Schizophrenia is associated with cognitive and behavioral dysfunctions thought to reflect imbalances in neurotransmission systems. Recent screenings suggested that lack of (functional) syndapin I (PACSIN1) may be linked to schizophrenia. We therefore studied syndapin I KO mice to address the suggested causal relationship to schizophrenia and to analyze associated molecular, cellular, and neurophysiological defects. Syndapin I knockout (KO) mice developed schizophrenia-related behaviors, such as hyperactivity, reduced anxiety, reduced response to social novelty, and an exaggerated novel object response and exhibited defects in dendritic arborization in the cortex. Neuromorphogenic deficits were also observed for a schizophrenia-associated syndapin I mutant in cultured neurons and coincided with a lack of syndapin I–mediated membrane recruitment of cytoskeletal effectors. Syndapin I KO furthermore caused glutamatergic hypofunctions. Syndapin I regulated both AMPAR and NMDAR availabilities at synapses during basal synaptic activity and during synaptic plasticity—particularly striking were a complete lack of long-term potentiation and defects in long-term depression in syndapin I KO mice. These synaptic plasticity defects coincided with alterations of postsynaptic actin dynamics, synaptic GluA1 clustering, and GluA1 mobility. Both GluA1 and GluA2 were not appropriately internalized. Summarized, syndapin I KO led to schizophrenia-like behavior, and our analyses uncovered associated molecular and cellular mechanisms.

scholarly journals Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory

2003 ◽  
Vol 358 (1432) ◽  
pp. 773-786 ◽  
Author(s):  
R. G. M. Morris ◽  
E. I. Moser ◽  
G. Riedel ◽  
S. J. Martin ◽  
J. Sandin ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Cellular Mechanisms ◽  
Memory Processing ◽  
Functional Studies ◽  
Term Potentiation ◽  
Intermediate Storage ◽  
Activity Dependent

The hypothesis that synaptic plasticity is a critical component of the neural mechanisms underlying learning and memory is now widely accepted. In this article, we begin by outlining four criteria for evaluating the ‘synaptic plasticity and memory (SPM)’ hypothesis. We then attempt to lay the foundations for a specific neurobiological theory of hippocampal (HPC) function in which activity-dependent synaptic plasticity, such as long-term potentiation (LTP), plays a key part in the forms of memory mediated by this brain structure. HPC memory can, like other forms of memory, be divided into four processes: encoding, storage, consolidation and retrieval. We argue that synaptic plasticity is critical for the encoding and intermediate storage of memory traces that are automatically recorded in the hippocampus. These traces decay, but are sometimes retained by a process of cellular consolidation. However, we also argue that HPC synaptic plasticity is not involved in memory retrieval, and is unlikely to be involved in systems-level consolidation that depends on HPC-neocortical interactions, although neocortical synaptic plasticity does play a part. The information that has emerged from the worldwide focus on the mechanisms of induction and expression of plasticity at individual synapses has been very valuable in functional studies. Progress towards a comprehensive understanding of memory processing will also depend on the analysis of these synaptic changes within the context of a wider range of systems-level and cellular mechanisms of neuronal transmission and plasticity.

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