scholarly journals Interactions between calmodulin and neurogranin govern the dynamics of CaMKII as a leaky integrator

2019 ◽  
Author(s):  
Mariam Ordyan ◽  
Tom Bartol ◽  
Mary Kennedy ◽  
Padmini Rangamani ◽  
Terrence Sejnowski
Keyword(s):  
Long Term Potentiation ◽  
Time Averaging ◽  
Calcium Signals ◽  
Term Potentiation ◽  
High Calcium ◽  
Leaky Integrator ◽  
Voltage Dependent ◽  
High Calcium Concentration ◽  
Voltage Dependent Calcium Channels

AbstractCalmodulin-dependent kinase II (CaMKII) has long been known to play an important role in learning and memory as well as long term potentiation (LTP). More recently it has been suggested that it might be involved in the time averaging of synaptic signals, which can then lead to the high precision of information stored at a single synapse. However, the role of the scaffolding molecule, neurogranin (Ng), in governing the dynamics of CaMKII is not yet fully understood. In this work, we adopt a rule-based modeling approach through the Monte Carlo method to study the effect of Ca2+ signals on the dynamics of CaMKII phosphorylation in the postsynaptic density (PSD). Calcium surges are observed in synaptic spines during an EPSP and back-propagating action potential due to the opening of NMDA receptors and voltage dependent calcium channels. We study the differences between the dynamics of phosphorylation of CaMKII monomers and dodecameric holoenzymes. The scaffolding molecule Ng, when present in significant concentration, limits the availability of free calmodulin (CaM), the protein which activates CaMKII in the presence of calcium. We show that it plays an important modulatory role in CaMKII phosphorylation following a surge of high calcium concentration. We find a non-intuitive dependence of this effect on CaM concentration that results from the different affinities of CaM for CaMKII depending on the number of calcium ions bound to the former. It has been shown previously that in the absence of phosphatase CaMKII monomers integrate over Ca2+ signals of certain frequencies through autophosphorylation (Pepke et al, Plos Comp. Bio., 2010). We also study the effect of multiple calcium spikes on CaMKII holoenzyme autophosphorylation, and show that in the presence of phosphatase CaMKII behaves as a leaky integrator of calcium signals, a result that has been recently observed in vivo. Our models predict that the parameters of this leaky integrator are finely tuned through the interactions of Ng, CaM, CaMKII, and PP1. This is a possible mechanism to precisely control the sensitivity of synapses to calcium signals.

Distinct LTP induction mechanisms: contribution of NMDA receptors and voltage-dependent calcium channels

1995 ◽  
Vol 73 (1) ◽  
pp. 270-279 ◽  
Author(s):  
K. M. Huber ◽  
M. D. Mauk ◽  
P. T. Kelly
Keyword(s):  
Nmda Receptor ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Nmda Receptor Antagonist ◽  
K Channel ◽  
Combined Application ◽  
Term Potentiation ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

1. Our results indicate that there are two distinct components of long-term potentiation (LTP) induced by the K+ channel blocker tetraethylammonium chloride (TEA) at synapses of hippocampal CA1 pyramidal neurons. Preincubation of hippocampal slices in the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5 phosphonovalerate (D,L-APV, 50 microM), reduced the magnitude of TEA LTP. In addition, the L-type voltage-dependent Ca2+ channel (VDCC) antagonist nifedipine (10 microM) attenuated TEA LTP. Only the combined application of D,L-APV plus nifedipine blocked the induction of TEA LTP. 2. Occlusion experiments demonstrated that saturation of VDCC-dependent TEA LTP did not reduce or occlude NMDA-receptor-dependent TEA LTP. These results indicate that the mechanisms underlying VDCC and NMDA receptor components of TEA LTP are different and do not share a common saturable mechanism. 3. TEA LTP was strictly dependent on NMDA receptor activity in slices with CA3-CA1 connections severed (isolated CA1 slices). In contrast to results obtained in slices with intact CA3-CA1 connections, the NMDA receptor antagonists APV (50 microM) or MK-801 dizocilpine (10 microM) completely blocked TEA LTP in isolated CA1. Consistent with this observation, the properties of TEA LTP in isolated CA1 were very similar to other types of NMDA-receptor-dependent plasticity such as tetanus-induced LTP; TEA LTP required presynaptic stimulation, displayed pathway specificity, and was occluded by tetanus-induced LTP.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals VDCCs and NMDARs Underlie Two Forms of LTP in CA1 Hippocampus In Vivo

1999 ◽  
Vol 82 (2) ◽  
pp. 736-740 ◽  
Author(s):  
S. L. Morgan ◽  
T. J. Teyler
Keyword(s):  
Long Term Potentiation ◽  
Stratum Radiatum ◽  
Mk 801 ◽  
Aspartate Receptor ◽  
Area Ca1 ◽  
Term Potentiation ◽  
Voltage Dependent

N-methyl-d-aspartate receptor/channel (NMDAR) and voltage-dependent calcium channel (VDCC) antagonists applied independently reduce the magnitude of long-term potentiation (LTP) in area CA1 of the hippocampal slice preparation. When used in combination, the antagonists completely block the induction of LTP. In urethan-anesthetized rats we examined the effect of the NMDAR blocker MK-801 (0.1 mg/kg) and the VDCC blocker Verapamil (10 mg/kg) on LTP induction in area CA1. Extracellular recordings were obtained from stratum radiatum following stimulation of Schaffer collaterals. LTP was induced by a 200-Hz/100-ms tetanus repeated 10 times (2 s isi). Tetanus was given in the presence of intraperitoneal saline, MK-801, Verapamil, or both Verapamil and MK-801. When given separately, Verapamil and MK-801 both significantly reduced the magnitude of LTP as compared with control animals. When given together, the drugs blocked the induction of LTP completely. We conclude that like LTP in vitro, VDCCs and NMDAR underlie two forms of LTP in vivo.

Electrical Stimuli Patterned After the Theta-Rhythm Induce Multiple Forms of LTP

2001 ◽  
Vol 86 (3) ◽  
pp. 1289-1296 ◽  
Author(s):  
S. L. Morgan ◽  
T. J. Teyler
Keyword(s):  
Calcium Influx ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
High Frequency Stimulation ◽  
Natural Activity ◽  
Term Potentiation ◽  
Voltage Dependent ◽  
Acceptable Model ◽  
Voltage Dependent Calcium Channels ◽  
Frequency Stimulation

The induction of long-term potentiation (LTP) by high-frequency stimulation is considered an acceptable model for the study of learning and memory. In area CA1 calcium influx through N-methyl-d-aspartate receptors (NMDARs; nmdaLTP) and/or L-type voltage-dependent calcium channels (vdccLTP) results in distinct forms of LTP. In the light of significant accumulation of knowledge about patterns of naturally occurring activity in the intact animal, we examined whether the application of stimuli patterned after natural activity induced nmdaLTP and/or vdccLTP. In rat hippocampal slices we examined LTP induced by three types of patterned stimulation short (S-TBS), long (L-TBS), and high-intensity long theta-patterned stimulation (HL-TBS). The patterns of stimulation were applied in control, nifedipine (blocks vdccLTP),d,l-2-amino-5-phosphonovaleric acid (APV; blocks nmdaLTP), or APV and nifedipine containing media. We found that S-TBS resulted in LTP that was completely attenuated in the presence of APV but was unaffected by nifedipine. Thus S-TBS results in the selective induction of nmdaLTP. L-TBS resulted in LTP that was completely blocked by APV and only partially blocked by nifedipine. Therefore L-TBS results in a compoundLTP consisting of both nmdaLTP and vdccLTP components. In the presence of APV, HL-TBS resulted in vdccLTP, and when APV and nifedipine were both present, LTP was completely blocked. Thus HL-TBS results in a vdccLTP in isolation when APV is present. We also examined saturation of S-TBS–induced LTP (nmdaLTP) by applying S-TBS at short intervals. When nifedipine was present, multiple S-TBS trains resulted in a substantially smaller final LTP as compared with controls. We conclude that multiple bursts of S-TBS eventually summate to result in compoundLTP. Stimuli patterned after innate rhythms in the hippocampus effectively induce nmdaLTP (S-TBS), compoundLTP (L-TBS), or vdccLTP (HL-TBS).

Brivaracetam Prevents the Over-expression of Synaptic Vesicle Protein 2A and Rescues the Deficits of Hippocampal Long-term Potentiation In Vivo in Chronic Temporal Lobe Epilepsy Rats

2020 ◽  
Vol 17 (4) ◽  
pp. 354-360 ◽  
Author(s):  
Yu-Xing Ge ◽  
Ying-Ying Lin ◽  
Qian-Qian Bi ◽  
Yu-Juan Chen
Keyword(s):  
Synaptic Plasticity ◽  
Temporal Lobe Epilepsy ◽  
Synaptic Vesicle ◽  
Long Term Potentiation ◽  
Synaptic Dysfunction ◽  
Over Expression ◽  
Term Potentiation ◽  
Synaptic Vesicle Protein 2A

Background: Patients with temporal lobe epilepsy (TLE) usually suffer from cognitive deficits and recurrent seizures. Brivaracetam (BRV) is a novel anti-epileptic drug (AEDs) recently used for the treatment of partial seizures with or without secondary generalization. Different from other AEDs, BRV has some favorable properties on synaptic plasticity. However, the underlying mechanisms remain elusive. Objective: The aim of this study was to explore the neuroprotective mechanism of BRV on synaptic plasticity in experimental TLE rats. Methods: The effect of chronic treatment with BRV (10 mg/kg) was assessed on Pilocarpine induced TLE model through measurement of the field excitatory postsynaptic potentials (fEPSPs) in vivo. Differentially expressed synaptic vesicle protein 2A (SV2A) were identified with immunoblot. Then, fast phosphorylation of synaptosomal-associated protein 25 (SNAP-25) during long-term potentiation (LTP) induction was performed to investigate the potential roles of BRV on synaptic plasticity in the TLE model. Results: An increased level of SV2A accompanied by a depressed LTP in the hippocampus was shown in epileptic rats. Furthermore, BRV treatment continued for more than 30 days improved the over-expression of SV2A and reversed the synaptic dysfunction in epileptic rats. Additionally, BRV treatment alleviates the abnormal SNAP-25 phosphorylation at Ser187 during LTP induction in epileptic ones, which is relevant to the modulation of synaptic vesicles exocytosis and voltagegated calcium channels. Conclusion: BRV treatment ameliorated the over-expression of SV2A in the hippocampus and rescued the synaptic dysfunction in epileptic rats. These results identify the neuroprotective effect of BRV on TLE model.

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