Impairments of Long-Term Synaptic Plasticity in the Hippocampus of Young Rats during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

Status epilepticus (SE) causes persistent abnormalities in the functioning of neuronal networks, often resulting in worsening epileptic seizures. Many details of cellular and molecular mechanisms of seizure-induced changes are still unknown. The lithium–pilocarpine model of epilepsy in rats reproduces many features of human temporal lobe epilepsy. In this work, using the lithium–pilocarpine model in three-week-old rats, we examined the morphological and electrophysiological changes in the hippocampus within a week following pilocarpine-induced seizures. We found that almost a third of the neurons in the hippocampus and dentate gyrus died on the first day, but this was not accompanied by impaired synaptic plasticity at that time. A diminished long-term potentiation (LTP) was observed following three days, and the negative effect of SE on plasticity increased one week later, being accompanied by astrogliosis. The attenuation of LTP was caused by the weakening of N-methyl-D-aspartate receptor (NMDAR)-dependent signaling. NMDAR-current was more than two-fold weaker during high-frequency stimulation in the post-SE rats than in the control group. Application of glial transmitter D-serine, a coagonist of NMDARs, allows the enhancement of the NMDAR-dependent current and the restoration of LTP. These results suggest that the disorder of neuron–astrocyte interactions plays a critical role in the impairment of synaptic plasticity.

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Levetiracetam Reduced the Basal Excitability of the Dentate Gyrus without Restoring Impaired Synaptic Plasticity in Rats with Temporal Lobe Epilepsy

Brain Sciences ◽

10.3390/brainsci10090634 ◽

2020 ◽

Vol 10 (9) ◽

pp. 634

Author(s):

Guillermo González-H ◽

Itzel Jatziri Contreras-García ◽

Karla Sánchez-Huerta ◽

Claudio M. T. Queiroz ◽

Luis Ricardo Gallardo Gudiño ◽

...

Keyword(s):

Synaptic Plasticity ◽

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Focal Epilepsy ◽

Chronic Phase ◽

Long Term Potentiation ◽

Excitatory Postsynaptic Potential ◽

Output Curve

Temporal lobe epilepsy (TLE), the most common type of focal epilepsy, affects learning and memory; these effects are thought to emerge from changes in synaptic plasticity. Levetiracetam (LEV) is a widely used antiepileptic drug that is also associated with the reversal of cognitive dysfunction. The long-lasting effect of LEV treatment and its participation in synaptic plasticity have not been explored in early chronic epilepsy. Therefore, through the measurement of evoked field potentials, this study aimed to comprehensively identify the alterations in the excitability and the short-term (depression/facilitation) and long-term synaptic plasticity (long-term potentiation, LTP) of the dentate gyrus of the hippocampus in a lithium–pilocarpine rat model of TLE, as well as their possible restoration by LEV (1 week; 300 mg/kg/day). TLE increased the population spike (PS) amplitude (input/output curve); interestingly, LEV treatment partially reduced this hyperexcitability. Furthermore, TLE augmented synaptic depression, suppressed paired-pulse facilitation, and reduced PS-LTP; however, LEV did not alleviate such alterations. Conversely, the excitatory postsynaptic potential (EPSP)-LTP of TLE rats was comparable to that of control rats and was decreased by LEV. LEV caused a long-lasting attenuation of basal hyperexcitability but did not restore impaired synaptic plasticity in the early chronic phase of TLE.

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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

Current Neurovascular Research ◽

10.2174/1567202617666200514114917 ◽

2020 ◽

Vol 17 (4) ◽

pp. 354-360 ◽

Cited By ~ 1

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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Tau- but not Aß -pathology enhances NMDAR-dependent depotentiation in AD-mouse models

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0813-4 ◽

2019 ◽

Vol 7 (1) ◽

Author(s):

Enrico Faldini ◽

Tariq Ahmed ◽

Luc Bueé ◽

David Blum ◽

Detlef Balschun

Keyword(s):

Synaptic Plasticity ◽

Transgenic Mice ◽

Mouse Models ◽

Long Term Potentiation ◽

High Frequency Stimulation ◽

Synaptic Loss ◽

Ca1 Region ◽

Term Potentiation ◽

Frequency Stimulation

AbstractMany mouse models of Alzheimer’s disease (AD) exhibit impairments in hippocampal long-term-potentiation (LTP), seemingly corroborating the strong correlation between synaptic loss and cognitive decline reported in human studies. In other AD mouse models LTP is unaffected, but other defects in synaptic plasticity may still be present. We recently reported that THY-Tau22 transgenic mice, that overexpress human Tau protein carrying P301S and G272 V mutations and show normal LTP upon high-frequency-stimulation (HFS), develop severe changes in NMDAR mediated long-term-depression (LTD), the physiological counterpart of LTP. In the present study, we focused on putative effects of AD-related pathologies on depotentiation (DP), another form of synaptic plasticity. Using a novel protocol to induce DP in the CA1-region, we found in 11–15 months old male THY-Tau22 and APPPS1–21 transgenic mice that DP was not deteriorated by Aß pathology while significantly compromised by Tau pathology. Our findings advocate DP as a complementary form of synaptic plasticity that may help in elucidating synaptic pathomechanisms associated with different types of dementia.

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Synaptic mechanisms underlying thalamic activation-induced plasticity in the rat auditory cortex

Journal of Neurophysiology ◽

10.1152/jn.00180.2013 ◽

2014 ◽

Vol 111 (9) ◽

pp. 1746-1758 ◽

Cited By ~ 1

Author(s):

Zhi-ru Zhu ◽

Fenglian Xu ◽

Wei-gang Ji ◽

Shuan-cheng Ren ◽

Fang Chen ◽

...

Keyword(s):

Synaptic Plasticity ◽

Auditory Cortex ◽

Frequency Tuning ◽

Long Term Potentiation ◽

High Frequency Stimulation ◽

Excitatory Postsynaptic Currents ◽

Postsynaptic Currents ◽

Medial Geniculate ◽

Synaptic Mechanisms

Electrical stimulation of ventral division of medial geniculate body (MGBv) neurons evokes a shift of the frequency-tuning curves of auditory cortical (AC) neurons toward the best frequency (BF) of the stimulated MGBv neurons (frequency-specific plasticity). The shift of BF is induced by inhibition of responses at the BF of the recorded AC neuron, with coincident facilitation of responses at the BF of the stimulated MGBv neuron. However, the synaptic mechanisms are not yet understood. We hypothesize that activation of thalamocortical synaptic transmission and receptor function may contribute to MGBv stimulation-induced frequency-specific auditory plasticity and the shift of BF. To test this hypothesis, we measured changes in the excitatory postsynaptic currents in pyramidal neurons of layer III/IV in the auditory cortex following high-frequency stimulation (HFS) of the MGBv, using whole cell recordings in an auditory thalamocortical slice. Our data showed that in response to the HFS of the MGBv the excitatory postsynaptic currents of AC neurons showed long-term bidirectional synaptic plasticity and long-term potentiation and depression. Pharmacological studies indicated that the long-term synaptic plasticity was induced through the activation of different sets of N-methyl-d-aspartate-type glutamatergic receptors, γ-aminobutyric acid-type receptors, and type 5 metabotropic glutamate receptors. Our data further demonstrated that blocking of different receptors with specific antagonists significantly inhibited MGBv stimulation-induced long-term plasticity as well as the shift of BF. These data indicate that these receptors have an important role in mediating frequency-specific auditory cortical plasticity.

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Specific Roles of AMPA Receptor Subunit GluR1 (GluA1) Phosphorylation Sites in Regulating Synaptic Plasticity in the CA1 Region of Hippocampus

Journal of Neurophysiology ◽

10.1152/jn.00835.2009 ◽

2010 ◽

Vol 103 (1) ◽

pp. 479-489 ◽

Cited By ~ 143

Author(s):

Hey-Kyoung Lee ◽

Kogo Takamiya ◽

Kaiwen He ◽

Lihua Song ◽

Richard L. Huganir

Keyword(s):

Synaptic Plasticity ◽

Critical Role ◽

Long Term Potentiation ◽

Phosphorylation Sites ◽

Ca1 Region ◽

Term Potentiation ◽

Ampa Receptor Subunit ◽

Glur1 Subunit ◽

Activity Dependent

Activity-dependent changes in excitatory synaptic transmission in the CNS have been shown to depend on the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). In particular, several lines of evidence suggest that reversible phosphorylation of AMPAR subunit glutamate receptor 1 (GluR1, also referred to as GluA1 or GluR-A) plays a role in long-term potentiation (LTP) and long-term depression (LTD). We previously reported that regulation of serines (S) 831 and 845 on the GluR1 subunit may play a critical role in bidirectional synaptic plasticity in the Schaffer collateral inputs to CA1. Specifically, gene knockin mice lacking both S831 and S845 phosphorylation sites (“double phosphomutants”), where both serine residues were replaced by alanines (A), showed a faster decaying LTP and a deficit in LTD. To determine which of the two phosphorylation sites was responsible for the phenotype, we have now generated two lines of gene knockin mice: one that specifically lacks S831 (S831A mutants) and another that lacks only S845 (S845A mutants). We found that S831A mutants display normal LTP and LTD, whereas S845A mutants show a specific deficit in LTD. Taken together with our previous results from the “double phosphomutants,” our data suggest that either S831 or S845 alone may support LTP, whereas the S845 site is critical for LTD expression.

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Dissecting the Roles of Kalirin-7/PSD95/GluN2B Interactions in Different Forms of Synaptic Plasticity

10.1101/744508 ◽

2019 ◽

Author(s):

Mason L. Yeh ◽

Jessica R. Yasko ◽

Eric S. Levine ◽

Betty A. Eipper ◽

Richard E. Mains

Keyword(s):

Synaptic Plasticity ◽

Knockout Mice ◽

Molecular Mechanisms ◽

Postsynaptic Density ◽

Long Term Potentiation ◽

Surface Expression ◽

Multiple Components ◽

Term Potentiation ◽

Knockout Animals

AbstractKalirin-7 (Kal7) is a Rac1/RhoG GEF and multidomain scaffold localized to the postsynaptic density which plays an important role in synaptic plasticity. Behavioral and physiological phenotypes observed in the Kal7 knockout mouse are quite specific: genetics of breeding, growth, strength and coordination are normal; Kal7 knockout animals self-administer cocaine far more than normal mice, show exaggerated locomotor responses to cocaine, but lack changes in dendritic spine morphology seen in wildtype mice; Kal7 knockout mice have depressed surface expression of GluN2B receptor subunits and exhibit marked suppression of long-term potentiation and depression in hippocampus, cerebral cortex, and spinal cord; and Kal7 knockout mice have dramatically blunted perception of pain. To address the underlying cellular and molecular mechanisms which are deranged by loss of Kal7, we administered intracellular blocking peptides to acutely change Kal7 function at the synapse, to determine if plasticity deficits in Kal7-/-mice are the product of developmental processes since conception, or could be detected on a much shorter time scale. We found that specific disruption of the interactions of Kal7 with PSD-95 or GluN2B resulted in significant suppression of long-term potentiation and long-term depression. Biochemical approaches indicated that Kal7 interacted with PSD-95 at multiple sites within Kal7.Graphical Table of ContentsThe postsynaptic density is an integral player in receiving, interpreting and storing signals transmitted by presynaptic terminals. The correct molecular composition is crucial for successful expression of synaptic plasticity. Key components of the postsynaptic density include ligand-gated ion channels, structural and binding proteins, and multidomain scaffolding plus enzymatic proteins. These studies address whether the multiple components of the synaptic density bind together in a static or slowly adapting molecular complex, or whether critical interactions are fluid on a minute-to-minute basis.

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Chronic neuronal excitation leads to homeostatic suppression of structural long-term potentiation

10.1101/2021.03.16.435575 ◽

2021 ◽

Author(s):

Hiromi H Ueda ◽

Aiko Sato ◽

Maki Onda ◽

Hideji Murakoshi

Keyword(s):

Synaptic Plasticity ◽

Molecular Mechanisms ◽

Long Term Potentiation ◽

Homeostatic Plasticity ◽

Ca1 Neurons ◽

Downstream Signaling ◽

Neuronal Excitation ◽

Term Potentiation ◽

Hippocampal Ca1

Synaptic plasticity is long-lasting changes in synaptic currents and structure. When neurons are exposed to signals that induce aberrant neuronal excitation, they increase the threshold for the induction of synaptic plasticity, called homeostatic plasticity. To further understand the homeostatic regulation of synaptic plasticity and its molecular mechanisms, we investigated glutamate uncaging/photoactivatable (pa)CaMKII-dependent sLTP induction in hippocampal CA1 neurons after chronic neuronal excitation by GABAA receptor antagonists. The neuronal excitation suppressed the glutamate uncaging-evoked Ca2+ influx and failed to induce sLTP. Single-spine optogenetic stimulation using paCaMKII also failed to induce sLTP, suggesting that CaMKII downstream signaling is impaired in response to chronic neuronal excitation. Furthermore, while the inhibition of Ca2+ influx was protein synthesis-independent, paCaMKII-induced sLTP depended on it. Our findings demonstrate that chronic neuronal excitation suppresses sLTP in two independent ways (i.e., the inhibitions of Ca2+ influx and CaMKII downstream signaling), which may contribute to the robust neuronal protection in excitable environments.

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

10.21203/rs.3.rs-41613/v1 ◽

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.

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THE EFFECT OF PROTEASE-ACTIVATED RECEPTORS 1 INHIBITION ON DEPRESSIVE-LIKE BEHAVIOR IN THE LATENT STAGE OF FORMATION OF TEMPORAL LOBE EPILEPSY

Fiziolohichnyĭ zhurnal ◽

10.15407/fz66.05.017 ◽

2020 ◽

Vol 66 (5) ◽

pp. 17-22

Author(s):

М. Semenikhina ◽

◽

M. Fedoryuk ◽

R. Bogovik ◽

◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Forced Swim Test ◽

Preference Test ◽

Control Group ◽

Protease Activated Receptors ◽

Swim Test ◽

Latent Stage ◽

Forced Swim ◽

Pilocarpine Model

Here we investigate the effect of pharmacological blockade of protease-activated receptors 1 (PAR1) on depressive-like behavioral impairments following status epilepticus (SE). Behavioral tests were performed during the latent stage of formation of temporal lobe epilepsy two weeks after SE induced using lithium-pilocarpine model. The PAR1 blocker (SCH 79797) was injected for 10 days after SE. The results indicate a partial normalization of depressive-like behavior in the forced swim test: the climbing time was 180 s after PAR1 inhibition, and 87 s after SE). We also observed behavioral normalization after PAR1 inhibition in the sucrose test. PAR1 inhibition led to the normalization of climbing time in the forced swim test, as well as normalized the behavior in the sucrose preference test. At the same time, the swimming time in the forced swim test decreased due to the PAR1 inhibition compared to the control group, while the floating time increased.

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A Unique Mouse Model of Early Life Exercise Enables Hippocampal Memory and Synaptic Plasticity

10.1101/699603 ◽

2019 ◽

Author(s):

Autumn S. Ivy ◽

Tim Yu ◽

Enikö Kramár ◽

Sonia Parievsky ◽

Fred Sohn ◽

...

Keyword(s):

Synaptic Plasticity ◽

Early Life ◽

Molecular Mechanisms ◽

Memory Task ◽

Long Term Potentiation ◽

Long Term Memory ◽

Critical Periods ◽

Juvenile Period ◽

Cognitive Benefits

AbstractAerobic exercise is a powerful modulator of learning and memory. Molecular mechanisms underlying the cognitive benefits of exercise are well documented in adult rodents. Animal models of exercise targeting specific postnatal periods of hippocampal development and plasticity are lacking. Here we characterize a model of early-life exercise (ELE) in male and female mice designed with the goal of identifying critical periods by which exercise may have a lasting impact on hippocampal memory and synaptic plasticity. Mice freely accessed a running wheel during three postnatal periods: the 4th postnatal week (juvenile ELE, P21-27), 6th postnatal week (adolescent ELE, P35-41), or 4th-6th postnatal weeks (juvenile-adolescent ELE, P21-41). All exercise groups significantly increased their running distances over time. When exposed to a weak learning stimulus, mice that had exercised during the juvenile period were able to form lasting long-term memory for a hippocampus-dependent spatial memory task. Electrophysiological experiments revealed enhanced long-term potentiation in hippocampal CA1 the juvenile-adolescent ELE group only. Furthermore, basal synaptic transmission was significantly increased in all mice that exercised during the juvenile period. Our results suggest early-life exercise can enable hippocampal memory, synaptic plasticity, and basal synaptic physiology when occurring during postnatal periods of hippocampal maturation.

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