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