scholarly journals Clmp Regulates AMPA and Kainate Receptor Responses in the Neonatal Hippocampal CA3 and Kainate Seizure Susceptibility in Mice

2020 ◽  
Vol 12 ◽  
Author(s):  
Seil Jang ◽  
Esther Yang ◽  
Doyoun Kim ◽  
Hyun Kim ◽  
Eunjoon Kim
Keyword(s):  
Object Recognition ◽  
Fear Conditioning ◽  
Adhesion Molecules ◽  
Mossy Fiber ◽  
Synaptic Proteins ◽  
Kinetic Properties ◽  
Synapse Development ◽  
Seizure Susceptibility ◽  
Synaptic Currents ◽  
Hippocampal Ca3

Synaptic adhesion molecules regulate synapse development through trans-synaptic adhesion and assembly of diverse synaptic proteins. Many synaptic adhesion molecules positively regulate synapse development; some, however, exert negative regulation, although such cases are relatively rare. In addition, synaptic adhesion molecules regulate the amplitude of post-synaptic receptor responses, but whether adhesion molecules can regulate the kinetic properties of post-synaptic receptors remains unclear. Here we report that Clmp, a homophilic adhesion molecule of the Ig domain superfamily that is abundantly expressed in the brain, reaches peak expression at a neonatal stage (week 1) and associates with subunits of AMPA receptors (AMPARs) and kainate receptors (KARs). Clmp deletion in mice increased the frequency and amplitude of AMPAR-mediated miniature excitatory post-synaptic currents (mEPSCs) and the frequency, amplitude, and decay time constant of KAR-mediated mEPSCs in hippocampal CA3 neurons. Clmp deletion had minimal impacts on evoked excitatory synaptic currents at mossy fiber-CA3 synapses but increased extrasynaptic KAR, but not AMPAR, currents, suggesting that Clmp distinctly inhibits AMPAR and KAR responses. Behaviorally, Clmp deletion enhanced novel object recognition and susceptibility to kainate-induced seizures, without affecting contextual or auditory cued fear conditioning or pattern completion-based contextual fear conditioning. These results suggest that Clmp negatively regulates hippocampal excitatory synapse development and AMPAR and KAR responses in the neonatal hippocampal CA3 as well as object recognition and kainate seizure susceptibility in mice.

Kinetic properties of two anatomically distinct excitatory synapses in hippocampal CA3 pyramidal neurons

1991 ◽  
Vol 66 (3) ◽  
pp. 1010-1020 ◽  
Author(s):  
S. H. Williams ◽  
D. Johnston
Keyword(s):  
Time Constant ◽  
Decay Time ◽  
Rise Time ◽  
Mossy Fiber ◽  
Decay Time Constant ◽  
Kinetic Properties ◽  
Synaptic Current ◽  
Synaptic Currents ◽  
Hippocampal Ca3 ◽  
The Mean

1. We have investigated the kinetic properties of pharmacologically isolated excitatory synaptic currents in hippocampal CA3 neurons. Two distinct anatomic pathways, the commissural/associational (C/A) and the mossy fiber inputs, were compared to test the hypothesis derived from cable theory that distal inputs have slower kinetics than proximal inputs when measured at the soma. 2. Intracellular recordings were made from adult rat hippocampal slices using a single-electrode voltage clamp and low-resistance microelectrodes. A mixture of 10 microM picrotoxin and 10 microM bicuculine was used to block completely fast GABAergic inhibition. The slow inhibitory input was blocked by intracellular cesium. 3. The mean reversal potential of mossy fiber synaptic currents, -2.8 mV, was not significantly different from that of the C/A synaptic current, -1.4 mV. The mean 10-90% rise time of the mossy-fiber synaptic current [1.7 +/- 0.08 (SE) ms], however, was significantly faster than the C/A synaptic current (3.2 +/- 0.16 ms). Both mossy fiber and C/A synaptic-current decays were fit with a single exponential. The decay time constant of mossy fiber synaptic currents was also faster than that of the C/A excitatory postsynaptic current, 6.5 +/- 0.4 versus 10.1 +/- 0.8 ms. The mossy fiber synaptic current decay time constant showed little voltage dependence. 4. A modified shape index plot of synaptic current rise time versus decay time constant, normalized to membrane time constant, yielded a good linear relation for C/A synapses. A poorer correlation was observed for mossy fiber synapses. 5. Both synaptic currents could be fit by alpha functions. A representative value of alpha for the mossy fiber synapse was 295/s, and for the C/A was 172/s. 6. The rise time of the mossy fiber synaptic potential was significantly faster (5.3 ms) than the C/A (7.5 ms). The decay of both mossy fiber and C/A synaptic potentials was slower than the membrane time constant, suggesting that active currents may contribute to their falling phases. This prolongation was voltage dependent but insensitive to 2-amino-5-phosphonovaleric acid. 7. Our data provide a quantitative comparison of a proximal and a more distal synaptic input to CA3 hippocampal neurons. Distal inputs show slower kinetics than proximal synapses, as predicted. However, the voltage dependence of synaptic potential decays suggests that synaptic integration may be affected by active dendritic conductances.

Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy.

1999 ◽  
Vol 113 (5) ◽  
pp. 902-913 ◽  
Author(s):  
Cheryl D. Conrad ◽  
Ana María Magariños ◽  
Joseph E. LeDoux ◽  
Bruce S. McEwen
Keyword(s):  
Fear Conditioning ◽  
Restraint Stress ◽  
Repeated Restraint Stress ◽  
Hippocampal Ca3 ◽  
Dendritic Atrophy

scholarly journals Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer

2019 ◽  
Author(s):  
Nuno Apóstolo ◽  
Samuel N. Smukowski ◽  
Jeroen Vanderlinden ◽  
Giuseppe Condomitti ◽  
Vasily Rybakin ◽  
...  
Keyword(s):  
Cell Surface ◽  
Pyramidal Neurons ◽  
Mossy Fiber ◽  
Surface Protein ◽  
Guidance Cue ◽  
Hippocampal Ca3 ◽  
Cell Surface Interactions ◽  
Ca3 Pyramidal Neurons ◽  
Ca3 Neurons ◽  
Multiple Ligand

SummarySynaptic diversity is a key feature of neural circuits. The structural and functional diversity of closely spaced inputs converging on the same neuron suggests that cell-surface interactions are essential in organizing input properties. Here, we analyzed the cell-surface protein (CSP) composition of hippocampal mossy fiber (MF) inputs on CA3 pyramidal neurons to identify regulators of MF-CA3 synapse properties. We uncover a rich cell-surface repertoire that includes adhesion proteins, guidance cue receptors, extracellular matrix (ECM) proteins, and uncharacterized CSPs. Interactome screening reveals multiple ligand-receptor modules and identifies ECM protein Tenascin-R (TenR) as a ligand of the uncharacterized neuronal receptor IgSF8. Presynaptic Igsf8 deletion impairs MF-CA3 synaptic architecture and robustly decreases the density of bouton filopodia that provide feedforward inhibition of CA3 neurons. Consequently, loss of IgSF8 increases CA3 neuron excitability. Our findings identify IgSF8 as a regulator of CA3 microcircuit development and suggest that combinations of CSP modules define input identity.

scholarly journals Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits

2021 ◽  
Vol 17 (10) ◽  
pp. e1009435
Author(s):  
Luke Y. Prince ◽  
Travis Bacon ◽  
Rachel Humphries ◽  
Krasimira Tsaneva-Atanasova ◽  
Claudia Clopath ◽  
...  
Keyword(s):  
Granule Cells ◽  
Mossy Fiber ◽  
Pyramidal Cells ◽  
Recurrent Network ◽  
Memory Storage ◽  
Neuronal Ensembles ◽  
Hippocampal Ca3 ◽  
Ca3 Pyramidal Cells ◽  
Episodic Memories ◽  
Mossy Fiber Pathway

In the hippocampus, episodic memories are thought to be encoded by the formation of ensembles of synaptically coupled CA3 pyramidal cells driven by sparse but powerful mossy fiber inputs from dentate gyrus granule cells. The neuromodulators acetylcholine and noradrenaline are separately proposed as saliency signals that dictate memory encoding but it is not known if they represent distinct signals with separate mechanisms. Here, we show experimentally that acetylcholine, and to a lesser extent noradrenaline, suppress feed-forward inhibition and enhance Excitatory–Inhibitory ratio in the mossy fiber pathway but CA3 recurrent network properties are only altered by acetylcholine. We explore the implications of these findings on CA3 ensemble formation using a hierarchy of models. In reconstructions of CA3 pyramidal cells, mossy fiber pathway disinhibition facilitates postsynaptic dendritic depolarization known to be required for synaptic plasticity at CA3-CA3 recurrent synapses. We further show in a spiking neural network model of CA3 how acetylcholine-specific network alterations can drive rapid overlapping ensemble formation. Thus, through these distinct sets of mechanisms, acetylcholine and noradrenaline facilitate the formation of neuronal ensembles in CA3 that encode salient episodic memories in the hippocampus but acetylcholine selectively enhances the density of memory storage.

Involvement of the dopaminergic system in the consolidation of fear conditioning in hippocampal CA3 subregion

2015 ◽  
Vol 278 ◽  
pp. 527-534 ◽  
Author(s):  
Jia-Ling Wen ◽  
Li Xue ◽  
Run-Hua Wang ◽  
Zi-Xiang Chen ◽  
Yan-Wei Shi ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Dopaminergic System ◽  
Hippocampal Ca3

scholarly journals Cerebral Ischemia Causes Dysregulation of Synaptic Adhesion in Mouse Synaptosomes

2007 ◽  
Vol 28 (1) ◽  
pp. 99-110 ◽  
Author(s):  
Willard J Costain ◽  
Ingrid Rasquinha ◽  
Jagdeep K Sandhu ◽  
Peter Rippstein ◽  
Bogdan Zurakowski ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Adhesion Molecules ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Synaptic Proteins ◽  
Mrna Levels ◽  
Neuronal Nuclei ◽  
Protein Levels

Synaptic pathology is observed during hypoxic events in the central nervous system in the form of altered dendrite structure and conductance changes. These alterations are rapidly reversible, on the return of normoxia, but are thought to initiate subsequent neuronal cell death. To characterize the effects of hypoxia on regulators of synaptic stability, we examined the temporal expression of cell adhesion molecules (CAMs) in synaptosomes after transient middle cerebral artery occlusion (MCAO) in mice. We focused on events preceding the onset of ischemic neuronal cell death (< 48 h). Synaptosome preparations were enriched in synaptically localized proteins and were free of endoplasmic reticulum and nuclear contamination. Electron microscopy showed that the synaptosome preparation was enriched in spheres (≈650 nm in diameter) containing secretory vesicles and postsynaptic densities. Forebrain mRNA levels of synaptically located CAMs was unaffected at 3 h after MCAO. This is contrasted by the observation of consistent downregulation of synaptic CAMs at 20 h after MCAO. Examination of synaptosomal CAM protein content indicated that certain adhesion molecules were decreased as early as 3 h after MCAO. For comparison, synaptosomal Agrn protein levels were unaffected by cerebral ischemia. Furthermore, a marked increase in the levels of p-Ctnnb1 in ischemic synaptosomes was observed. p-Ctnnb1 was detected in hippocampal fiber tracts and in cornu ammonis 1 neuronal nuclei. These results indicate that ischemia induces a dysregulation of a subset of synaptic proteins that are important regulators of synaptic plasticity before the onset of ischemic neuronal cell death.

scholarly journals The STEP61 interactome reveals subunit-specific AMPA receptor binding and synaptic regulation

2019 ◽  
Vol 116 (16) ◽  
pp. 8028-8037 ◽  
Author(s):  
Sehoon Won ◽  
Salvatore Incontro ◽  
Yan Li ◽  
Roger A. Nicoll ◽  
Katherine W. Roche
Keyword(s):  
Ampa Receptors ◽  
Protein Tyrosine Phosphatase ◽  
Protein Phosphatase ◽  
Tyrosine Phosphatase ◽  
Hippocampal Slices ◽  
Specific Protein ◽  
Synaptic Proteins ◽  
Synaptic Currents ◽  
Synaptic Regulation ◽  
Binding Partners

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific protein phosphatase that regulates a variety of synaptic proteins, including NMDA receptors (NAMDRs). To better understand STEP’s effect on other receptors, we used mass spectrometry to identify the STEP61 interactome. We identified a number of known interactors, but also ones including the GluA2 subunit of AMPA receptors (AMPARs). We show that STEP61 binds to the C termini of GluA2 and GluA3 as well as endogenous AMPARs in hippocampus. The synaptic expression of GluA2 and GluA3 is increased in STEP-KO mouse brain, and STEP knockdown in hippocampal slices increases AMPAR-mediated synaptic currents. Interestingly, STEP61 overexpression reduces the synaptic expression and synaptic currents of both AMPARs and NMDARs. Furthermore, STEP61 regulation of synaptic AMPARs is mediated by lysosomal degradation. Thus, we report a comprehensive list of STEP61 binding partners, including AMPARs, and reveal a central role for STEP61 in differentially organizing synaptic AMPARs and NMDARs.

scholarly journals The role of GFAP and vimentin in learning and memory

2019 ◽  
Vol 400 (9) ◽  
pp. 1147-1156 ◽  
Author(s):  
Ulrika Wilhelmsson ◽  
Andrea Pozo-Rodrigalvarez ◽  
Marie Kalm ◽  
Yolanda de Pablo ◽  
Åsa Widestrand ◽  
...  
Keyword(s):  
Object Recognition ◽  
Fear Conditioning ◽  
Morris Water Maze ◽  
Exploratory Behavior ◽  
Water Maze ◽  
Trace Fear Conditioning ◽  
Memory Extinction ◽  
Post Traumatic ◽  
Trace Fear

Abstract Intermediate filaments (also termed nanofilaments) are involved in many cellular functions and play important roles in cellular responses to stress. The upregulation of glial fibrillary acidic protein (GFAP) and vimentin (Vim), intermediate filament proteins of astrocytes, is the hallmark of astrocyte activation and reactive gliosis in response to injury, ischemia or neurodegeneration. Reactive gliosis is essential for the protective role of astrocytes at acute stages of neurotrauma or ischemic stroke. However, GFAP and Vim were also linked to neural plasticity and regenerative responses in healthy and injured brain. Mice deficient for GFAP and vimentin (GFAP−/−Vim−/−) exhibit increased post-traumatic synaptic plasticity and increased basal and post-traumatic hippocampal neurogenesis. Here we assessed the locomotor and exploratory behavior of GFAP−/−Vim−/− mice, their learning, memory and memory extinction, by using the open field, object recognition and Morris water maze tests, trace fear conditioning, and by recording reversal learning in IntelliCages. While the locomotion, exploratory behavior and learning of GFAP−/−Vim−/− mice, as assessed by object recognition, the Morris water maze, and trace fear conditioning tests, were comparable to wildtype mice, GFAP−/−Vim−/− mice showed more pronounced memory extinction when tested in IntelliCages, a finding compatible with the scenario of an increased rate of reorganization of the hippocampal circuitry.

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