Okadaic acid attenuates short-term and long-term synaptic plasticity of hippocampal dentate gyrus neurons in rats

doi:10.1016/j.nlm.2019.01.007

Neurobiology of Learning and Memory

Volume 158, February 2019, Pages 24-31

https://doi.org/10.1016/j.nlm.2019.01.007 Get rights and content

Highlights

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Intracerebroventricular (i.c.v.) injection of okadaic acid (OKA) drastically attenuates fEPSP slope and population spike in hippocampal DG neurons.
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Intracerebroventricular injection of OKA significantly decreases the short-term and long-term synaptic plasticity of hippocampal DG neurons.
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Administration of OKA results in impaired short-term and long-term spatial memories in rats.

Abstract

Protein phosphorylation states have a pivotal role in regulation of synaptic plasticity and long-term modulation of synaptic transmission. Serine/threonine protein phosphatase 1 (PP1) and 2A (PP2A) have a critical effect on various regulatory mechanisms involved in synaptic plasticity, learning and memory. Okadaic acid (OKA), a potent inhibitor of PP1 and PP2A, reportedly leads to cognitive decline and Alzheimer’s disease (AD)-like pathology. The aim of this study was to examine the effect of OKA on electrophysiological characteristics of hippocampal dentate gyrus (DG) neurons in vivo. Male Wistar rats were divided into two control and OKA groups. OKA was injected intracerebroventricularly (i.c.v.) into lateral ventricles and after two weeks the long-term potentiation (LTP) and paired-pulse responses recorded from hippocampal perforant path-DG synapses in order to assess short-term and long-term synaptic plasticity. Results of this study revealed that OKA-induced inhibition of PP1 and PP2A activity drastically attenuates the field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude following paired pulse and high frequency stimulation (HFS) of hippocampal DG neurons indicating pre- and post-synaptic involvement in electrical activity of these neurons. Administration of OKA impaired the short-term and long-term spatial memories conducted by Y-maze and passive avoidance tests, respectively. OKA-induced attenuation in electrophysiological activity and consequent memory deficits also provide a beneficial tool for studying neurodegenerative disorders such as AD.

Introduction

Protein phosphorylation states catalyzed by different kinases and phosphatases have a pivotal role in regulation of synaptic transmission and neurotransmitter release (Genoux et al., 2002). Several proteins with their fundamental roles in axonal transport and synaptic transmission are modulated by their phosphorylation and dephosphorylation states (Linden and Routtenberg, 1989, Serrano et al., 2005). Dysregulation in this normal rate of phosphorylation or dephosphorylation may give rise to mechanisms responsible for certain pathological conditions (Gong, Liu, Grundke-Iqbal, & Iqbal, 2006).

Recent studies have demonstrated the critical role for serine/threonine protein phosphatase 1 (PP1) and 2A (PP2A) in various regulatory mechanisms involved in synaptic plasticity, learning, and memory (Mansuy and Shenolikar, 2006, Winder and Sweatt, 2001). Previous evidences have reported that the inhibition of these phosphatases may ultimately lead to cognitive decline and Alzheimer’s disease (AD)-like pathology such as extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (Kamat, Rai, & Nath, 2013). Decreased activity of PP2A has been shown in the brain of AD patients and it has been suggested that reduction in the activity of this enzyme may be an early critical event leading to memory deficits and cognitive dysfunction in AD pathogenesis (Johnson and Hartigan, 1999, Tanimukai et al., 2005).

Okadaic acid (OKA) is a potent and selective inhibitor of PP1 and PP2A activity. It has been shown that administration of OKA can lead to AD-like neuropathological alterations such as oxidative stress, neuroinflammation, mitochondrial dysfunction, and neuro-excitotoxicity (Kamat et al., 2013, Kamat et al., 2014b). Intracerebroventricular (i.c.v.) injection of OKA gives rise to Aβ deposition, tau hyperphosphorylation, and subsequent synaptic loss and memory impairments in rats. These all are known to impair long-term potentiation (LTP), a cellular basis of learning and a main form of synaptic plasticity in the hippocampus (Kamat et al., 2014a, Kamat and Nath, 2015). Although these capabilities introduced OKA as a powerful tool for studying various regulatory mechanisms involved in learning and memory in AD pathology, there is very limited information on the effect of OKA on hippocampal LTP. The experimental data on the role of PP1 and PP2A in synaptic strength are rather controversial. In contrast to the deleterious effect of OKA-induced PP1 and PP2A inhibition on learning and memory, a number of studies have reported that hippocampal LTP has been associated with both inhibition of PP-1 and decreased activity of the PP2A (Maalouf & Rho, 2008). These protein phosphatases are suggested to have an inhibitory action on LTP induction and hence may play a key role in regulating hippocampal synaptic plasticity (Winder & Sweatt, 2001). The inhibitory action is proposed to be suppressed by cAMP-PKA signaling pathway during expression of LTP. Meanwhile, PP1 is known to be needed for synaptic long-term depression (LTD) and is required to be inhibited for induction of LTP (Jouvenceau et al., 2006). Administration of selective PP1 inhibitor has been reported to improve learning and memory, and this effect is attributed to increased phosphorylation of intracellular substrates involved in LTP induction (Genoux et al., 2002). On the other hand, a large body of literature have shown the attenuating effect of OKA on learning and memory in rodents (He et al., 2001, Tian et al., 2004).

Taken together, the aim of this study was to examine the effect of OKA on electrophysiological characteristics of hippocampal dentate gyrus (DG) neurons. For this purpose, we set out to explore paired-pulse response and LTP of DG neurons and accordingly the short-term and long-term learning and memory following i.c.v. administration of OKA in rats.

Section snippets

Animals and treatments

Male Wistar rats (300–350 g) were obtained from Pasteur Institute of Iran and maintained at an ambient temperature of 22–24 °C under a 12 h light-dark cycle, with lights off at 7:00 p.m. Food and water provided ad libitum. The experiments carried out between 10 a.m. and 4 p.m. using protocols approved by the Research and Ethics Committee of Ardabil University of Medical Sciences and conducted under the recommended conditions of the Guide for the Care and Use of Laboratory Animals of the

Input/output (I/O) functions

The input–output (I/O) functions were assessed by systematic variation of the stimulus current (100–1000 µA) so as to evaluate synaptic potency before induction of LTP. The stimulus–response function refers to the relationship between the excitatory input and the probability of neural action potential generation. Two-way mixed ANOVA indicated that there is no significant difference between the groups in stimulus–response curves recorded from DG as fEPSP slope (F(1,12) = 0.65, p = 0.43) and PS

Discussion

The present study was designed to evaluate the electrophysiological synaptic plasticity of hippocampal dentate gyrus neurons and memory performance two weeks after i.c.v. administration of OKA in rats. Results of this study revealed that OKA as a potent inhibitor of PP1 and PP2A can drastically attenuate paired-pulse facilitation, a form of short-term synaptic plasticity, and long-term potentiation of hippocampal dentate gyrus neurons. Our behavioral study also showed impairment in learning and

Conclusion

In conclusion, the results of the current study indicate that i.c.v. administration of OKA, a potent PP1 and PP2A inhibitor, drastically attenuates fEPSP and PS amplitude recorded from hippocampal DG neurons following paired-pulse and high frequency stimulation indicating pre- and post-synaptic involvement in these neurons. OKA-induced attenuation in electrophysiological activity and memory deficits may also provide a beneficial tool for studying neurodegenerative disorders such as AD.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Acknowledgements

This article is extracted from the thesis of Mrs. Nasrin Hamidi, MSc student of physiology at the Department of Physiology, School of Medicine, and is supported financially by the Research Vice-Chancellor of the School of Medicine, Ardabil University of Medical Sciences.

References (44)

S. Babri et al.
Effect of troxerutin on synaptic plasticity of hippocampal dentate gyrus neurons in a β-amyloid model of Alzheimer׳ s disease: An electrophysiological study
European Journal of Pharmacology
(2014)
J. Bak et al.
Effect of rotation preference on spontaneous alternation behavior on Y maze and introduction of a new analytical method, entropy of spontaneous alternation
Behavioural Brain Research
(2017)
S.P. Braithwaite et al.
Protein phosphatases and Alzheimer’s disease
Progress in Molecular Biology and Translational Science
(2012)
D. Fioravante et al.
Short-term forms of presynaptic plasticity
Current Opinion in Neurobiology
(2011)
C.-X. Gong et al.
Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain implications for neurofibrillary degeneration in Alzheimer’s disease
Journal of Biological Chemistry
(2000)
P.K. Kamat et al.
Okadaic acid induced neurotoxicity: An emerging tool to study Alzheimer’s disease pathology
Neurotoxicology
(2013)
P.K. Kamat et al.
Okadaic acid-induced Tau phosphorylation in rat brain: Role of NMDA receptor
Neuroscience
(2013)
P.K. Kamat et al.
Mechanism of synapse redox stress in okadaic acid (ICV) induced memory impairment: Role of NMDA receptor
Neurochemistry International
(2014)
D.J. Linden et al.
The role of protein kinase C in long-term potentiation: A testable model
Brain Research Reviews
(1989)
I.M. Mansuy et al.
Protein serine/threonine phosphatases in neuronal plasticity and disorders of learning and memory
Trends in Neurosciences
(2006)

W. Morishita et al.

Regulation of synaptic strength by protein phosphatase 1

Neuron

(2001)

M. Nategh et al.

Inactivation of nucleus incertus impairs passive avoidance learning and long term potentiation of the population spike in the perforant path-dentate gyrus evoked field potentials in rats

Neurobiology of Learning and Memory

(2016)

D.L. Oberbeck et al.

Intra-amygdalar okadaic acid enhances conditioned taste aversion learning and CREB phosphorylation in rats

Brain Research

(2010)

P. Singh et al.

N-methyl-D-aspartate receptor mechanosensitivity is governed by C terminus of NR2B subunit

Journal of Biological Chemistry

(2012)

H. Tanimukai et al.

Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer’s disease

The American Journal of Pathology

(2005)

Q. Tian et al.

Injection of okadaic acid into the meynert nucleus basalis of rat brain induces decreased acetylcholine level and spatial memory deficit

Neuroscience

(2004)

C. Xu et al.

PKC activators enhance GABAergic neurotransmission and paired-pulse facilitation in hippocampal CA1 pyramidal neurons

Neuroscience

(2014)

P.B. Allen et al.

Protein phosphatase-1 regulation in the induction of long-term potentiation: Heterogeneous molecular mechanisms

Journal of Neuroscience

(2000)

S. Babri et al.

Effect of aggregated beta-Amyloid (1–42) on synaptic plasticity of hippocampal dentate gyrus granule cells in vivo

BioImpacts: BI

(2012)

S. Babri et al.

Protective effects of troxerutin on β-amyloid (1–42)-induced impairments of spatial learning and memory in rats

Neurophysiology

(2012)

Y.V. Dobryakova et al.

Administration of muscarinic antagonists induce changes in passive avoidance learning and in synaptic transmission in the CA1 area of the hippocampus

Acta Neurobiologiae Experimentalis

(2018)

C.J. Fox et al.

Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo

Hippocampus

(2006)

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Okadaic acid attenuates short-term and long-term synaptic plasticity of hippocampal dentate gyrus neurons in rats

Highlights

Abstract

Introduction

Section snippets

Animals and treatments

Input/output (I/O) functions

Discussion

Conclusion

Conflict of interest statement

Acknowledgements

European Journal of Pharmacology

Behavioural Brain Research

Progress in Molecular Biology and Translational Science

Current Opinion in Neurobiology

Journal of Biological Chemistry

Neurotoxicology

Neuroscience

Neurochemistry International

Brain Research Reviews

Trends in Neurosciences

Neuron

Neurobiology of Learning and Memory

Brain Research

Journal of Biological Chemistry

The American Journal of Pathology

Neuroscience

Neuroscience

Protein phosphatase-1 regulation in the induction of long-term potentiation: Heterogeneous molecular mechanisms

Journal of Neuroscience

Effect of aggregated beta-Amyloid (1–42) on synaptic plasticity of hippocampal dentate gyrus granule cells in vivo

BioImpacts: BI

Protective effects of troxerutin on β-amyloid (1–42)-induced impairments of spatial learning and memory in rats

Neurophysiology

Administration of muscarinic antagonists induce changes in passive avoidance learning and in synaptic transmission in the CA1 area of the hippocampus

Acta Neurobiologiae Experimentalis

Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo

Hippocampus