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 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.

scholarly journals Functional MRI of long-term potentiation: imaging network plasticity

2014 ◽  
Vol 369 (1633) ◽  
pp. 20130152 ◽  
Author(s):  
Efrén Álvarez-Salvado ◽  
Vicente Pallarés ◽  
Andrea Moreno ◽  
Santiago Canals
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Plastic Property ◽  
Cellular Level ◽  
Synaptic Activity ◽  
Long Term Memory ◽  
Cellular Mechanisms ◽  
Term Potentiation

Neurons are able to express long-lasting and activity-dependent modulations of their synapses. This plastic property supports memory and conveys an extraordinary adaptive value, because it allows an individual to learn from, and respond to, changes in the environment. Molecular and physiological changes at the cellular level as well as network interactions are required in order to encode a pattern of synaptic activity into a long-term memory. While the cellular mechanisms linking synaptic plasticity to memory have been intensively studied, those regulating network interactions have received less attention. Combining high-resolution fMRI and in vivo electrophysiology in rats, we have previously reported a functional remodelling of long-range hippocampal networks induced by long-term potentiation (LTP) of synaptic plasticity in the perforant pathway. Here, we present new results demonstrating an increased bilateral coupling in the hippocampus specifically supported by the mossy cell commissural/associational pathway in response to LTP. This fMRI-measured increase in bilateral connectivity is accompanied by potentiation of the corresponding polysynaptically evoked commissural potential in the contralateral dentate gyrus and depression of the inactive convergent commissural pathway to the ipsilateral dentate. We review these and previous findings in the broader context of memory consolidation.

scholarly journals Phosphorylation of the AMPAR-TARP Complex in Synaptic Plasticity

Proteomes ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 40 ◽  
Author(s):  
Joongkyu Park
Keyword(s):  
Synaptic Plasticity ◽  
Drug Addiction ◽  
Ampa Receptor ◽  
Long Term Potentiation ◽  
Synaptic Activity ◽  
Regulatory Proteins ◽  
Cellular Models ◽  
Brain Functions ◽  
Term Potentiation

Synaptic plasticity has been considered a key mechanism underlying many brain functions including learning, memory, and drug addiction. An increase or decrease in synaptic activity of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) complex mediates the phenomena as shown in the cellular models of synaptic plasticity, long-term potentiation (LTP), and depression (LTD). In particular, protein phosphorylation shares the spotlight in expressing the synaptic plasticity. This review summarizes the studies on phosphorylation of the AMPAR pore-forming subunits and auxiliary proteins including transmembrane AMPA receptor regulatory proteins (TARPs) and discusses its role in synaptic plasticity.

Estrogenic Regulation of Synaptic Actin Proteins and Plasticity

2020 ◽  
pp. 69-82
Author(s):  
Enikö A. Kramár
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Synaptic Strength ◽  
Adult Brain ◽  
Actin Dynamics ◽  
Signaling Cascade ◽  
Term Potentiation ◽  
Estrogenic Regulation ◽  
Estradiol Levels

Estrogens are rapid and potent facilitators of synaptic plasticity in the adult brain; however, the steps that link estrogens to factors that regulate synaptic strength remain unclear. The present chapter will first review the acute effects of 17β‎-estradiol on synaptic transmission and long-term potentiation (LTP). It will then describe a synaptic model used to study the substrates of LTP and provide evidence for the ability of estradiol to rapidly engage a selective actin signaling cascade associated with the consolidation of LTP. Finally, it will be shown that chronic reductions in estradiol levels disrupt LTP and actin dynamics but can be reversed by acute infusions of the hormone. It is concluded here that estradiol can promote learning-related plasticity by modifying the synaptic cytoskeleton.

Differential effect of FHM2 mutation on synaptic plasticity in distinct hippocampal regions

Cephalalgia ◽  
2019 ◽  
Vol 39 (10) ◽  
pp. 1333-1338 ◽  
Author(s):  
Antonio de Iure ◽  
Petra Mazzocchetti ◽  
Guendalina Bastioli ◽  
Barbara Picconi ◽  
Cinzia Costa ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Familial Hemiplegic Migraine ◽  
Loss Of Function ◽  
Hemiplegic Migraine ◽  
Term Potentiation ◽  
Atp1a2 Gene ◽  
Ca1 Area ◽  
Reduced Rate

Introduction Familial hemiplegic migraine 2 is a pathology linked to mutation of the ATP1A2 gene producing loss of function of the α2 Na+/K+-ATPase (NKA). W887R/+ knock-in (KI) mice are used to model the familial hemiplegic migraine 2 condition and are characterized by 50% reduced NKA expression in the brain and reduced rate of K+ and glutamate clearance by astrocytes. These alterations might, in turn, produce synaptic changes in synaptic transmission and plasticity. Memory and learning deficits observed in familial hemiplegic migraine patients could be ascribed to a possible alteration of hippocampal neuronal plasticity and measuring possible changes of long-term potentiation in familial hemiplegic migraine 2 KI mice might provide insights to strengthen this link. Results Here we have investigated synaptic plasticity in distinct hippocampal regions in familial hemiplegic migraine 2 KI mice. We show that the dentate gyrus long-term potentiation of familial hemiplegic migraine 2 mice is abnormally increased in comparison with control animals. Conversely, in the CA1 area, KI and WT mice express long-term potentiation of similar amplitude. Conclusions The familial hemiplegic migraine 2 KI mice show region-dependent hippocampal plasticity abnormality, which might underlie some of the memory deficits observed in familial migraine.

scholarly journals Dissecting the Roles of Kalirin-7/PSD-95/GluN2B Interactions in Different Forms of Synaptic Plasticity

2020 ◽  
Author(s):  
Mason L. Yeh ◽  
Jessica R Yasko ◽  
Eric S. Levine ◽  
Betty A. Eipper ◽  
Richard Mains
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Synaptic Function ◽  
Nucleotide Exchange ◽  
Long Term Depression ◽  
Term Potentiation ◽  
Knockout Animals

Abstract Background: Kalirin-7 (Kal7) is a multidomain scaffold and guanine nucleotide exchange factor localized to the postsynaptic density, where Kal7 is crucial for synaptic plasticity. Kal7 knockout mice exhibit marked suppression of long-term potentiation and long-term depression in hippocampus, cerebral cortex and spinal cord, with depressed surface expression of GluN2B receptor subunits and dramatically blunted perception of pain. Kal7 knockout animals show exaggerated locomotor responses to psychostimulants and self-administer cocaine more enthusiastically than wildtype mice. Results: To address the underlying cellular and molecular mechanisms which are deranged by loss of Kal7, we infused candidate intracellular interfering peptides to acutely challenge the synaptic function(s) of Kal7 with potential protein binding partners, to determine if plasticity deficits in Kal7-/- mice are the product of developmental processes since conception, or could be produced on a much shorter time scale. We demonstrated that these small intracellular peptides disrupted normal long-term potentiation and long-term depression, strongly suggesting that maintenance of established interactions of Kal7 with PSD-95 and/or GluN2B is crucial to synaptic plasticity. Conclusions: Blockade of the Kal7-GluN2B interaction was most effective at blocking long-term potentiation, but had no effect on long-term depression. Biochemical approaches indicated that Kal7 interacted with PSD-95 at multiple sites within Kal7.

scholarly journals Endocannabinoid dynamics gate spike-timing dependent depression and potentiation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yihui Cui ◽  
Ilya Prokin ◽  
Hao Xu ◽  
Bruno Delord ◽  
Stephane Genet ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Long Term Potentiation ◽  
Cellular Mechanism ◽  
Spike Timing ◽  
Long Term Depression ◽  
Term Potentiation ◽  
Short And Long Term

Synaptic plasticity is a cardinal cellular mechanism for learning and memory. The endocannabinoid (eCB) system has emerged as a pivotal pathway for synaptic plasticity because of its widely characterized ability to depress synaptic transmission on short- and long-term scales. Recent reports indicate that eCBs also mediate potentiation of the synapse. However, it is not known how eCB signaling may support bidirectionality. Here, we combined electrophysiology experiments with mathematical modeling to question the mechanisms of eCB bidirectionality in spike-timing dependent plasticity (STDP) at corticostriatal synapses. We demonstrate that STDP outcome is controlled by eCB levels and dynamics: prolonged and moderate levels of eCB lead to eCB-mediated long-term depression (eCB-tLTD) while short and large eCB transients produce eCB-mediated long-term potentiation (eCB-tLTP). Moreover, we show that eCB-tLTD requires active calcineurin whereas eCB-tLTP necessitates the activity of presynaptic PKA. Therefore, just like glutamate or GABA, eCB form a bidirectional system to encode learning and memory.

Long-Term Potentiation and Long-Term Depression

2018 ◽  
Author(s):  
Arianna Maffei
Keyword(s):  
Synaptic Plasticity ◽  
Neural Circuit ◽  
Long Term Potentiation ◽  
Synaptic Connections ◽  
Long Term Depression ◽  
Term Potentiation ◽  
Functional Implications ◽  
The Brain

Synaptic connections in the brain can change their strength in response to patterned activity. This ability of synapses is defined as synaptic plasticity. Long lasting forms of synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD), are thought to mediate the storage of information about stimuli or features of stimuli in a neural circuit. Since its discovery in the early 1970s, synaptic plasticity became a central subject of neuroscience, and many studies centered on understanding its mechanisms, as well as its functional implications.

Learning and Memory

The Neuron ◽  
2015 ◽  
pp. 489-528
Author(s):  
Irwin B. Levitan ◽  
Leonard K. Kaczmarek
Keyword(s):  
Learning And Memory ◽  
Molecular Mechanisms ◽  
Long Term Potentiation ◽  
Memory Formation ◽  
Spike Timing ◽  
Cellular Mechanisms ◽  
Long Term Depression ◽  
Nervous Systems ◽  
Term Potentiation

Psychologists have described different kinds of learning and memory, and there is an ongoing search for the physical basis of these distinctions and for the cellular and molecular mechanisms responsible. Because of the complexity of most nervous systems, the search has focused to a large extent on animals with relatively simple nervous systems and on reduced preparations. Common themes have emerged, such as the requirement for signaling pathways linked to calcium and cyclic AMP, and the fact that pathways used in normal development continue to be used for plasticity in adults. At the same time, it is clear that there is an enormous diversity of cellular mechanisms that contribute to short-term and long-term phases of memory formation. These include long-term potentiation (LTP), long-term depression (LTD), spike-timing dependent plasticity, synaptic tagging, and synaptic scaling. Each type of synaptic connection has its own personality such that, in response to a particular pattern of stimulation, one synapse may increase its postsynaptic receptors while another may expand its presynaptic terminals.

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.

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