Effect of ceftriaxone on paired-pulse response and long-term potentiation of hippocampal dentate gyrus neurons in rats with Alzheimer-like disease
Introduction
Glutamatergic systems play critical roles in cognition, and dysfunction of glutamatergic neurons can underlie many psychological and neurodegenerative disorders [1,2]. Glutamate mediates fast excitatory neurotransmission in part through activation of N-methyl-d-aspartate (NMDA) receptors and Ca2+ influx, which in turn initiate a cascade of events that ultimately lead to synaptic plasticity and memory formation [3]. Previous studies highlight the involvement of glutamatergic systems in early phases of neurodegenerative disorders such as Alzheimer's disease (AD) [4]. In AD, increased release of glutamate from presynaptic neurons and astrocytes, and decreased glutamate removal from the synaptic space give rise to over-stimulation of glutamate receptors and increases in the production of β-amyloid (Aβ) peptide, cell death and finally deterioration of learning and memory [5]. Increased Aβ levels can also induce further glutamate release from presynaptic neurons which exacerbates the excitotoxicity and results in the formation of neurofibrillary tangles (NFTs) [6]. Extracellular deposits of Aβ and intracellular NFTs are two main hallmarks of AD responsible for many pathological changes including impairment in hippocampal long-term potentiation (LTP) and facilitation of long-term depression (LTD), the two forms of synaptic plasticity associated with learning and memory [7,8].
A large body of work has shown the glutamate-mediated excitotoxicity and neurodegeneration are major contributors to cognitive dysfunction and cell death in AD. There is evidence that impairments in mechanisms of glutamate uptake contribute to excitotoxic processes described above. Specifically, a decrease in glutamate uptake function has been correlated with down-regulation of glutamate transporters in different regions of the AD brain [9]. Five glutamate transporters (GLTs), also called excitatory amino acid transporters (EAAT1-5), have been identified each of which can act to regulate levels of released glutamate in synapses [10]. Glutamate transporter-1 (GLT-1), also known as EAAT2, is the predominant glutamate transporter in neocortex and hippocampus being responsible for 80–90% of glutamate uptake in these regions [11]. This transporter is primarily expressed in perisynaptic processes of astrocytes and is believed to have a pivotal role in the elimination of excessive glutamate from synaptic spaces. Reduced expression of GLT-1 protein has been reported to be an early and prominent event in AD brains and likely contributes to increases in the production of Aβ [12].
It has been well stablished that ceftriaxone (CFT), a β-lactam antibiotic, selectively induces the up-regulation of glutamate transporter-1 (GLT-1) in different brain regions such as frontal cortex, hippocampus, amygdala and thalamus [13,14]. Accordingly, a logical therapeutic strategy to combat the onset and development of AD pathology would be to target glutamate uptake functions and thereby maintain synaptic glutamate at non-pathological levels. The present study was designed to test this approach and, specifically, to investigate whether administration of ceftriaxone could offset the emergence of behavioral and synaptic plasticity impairments in an animal model of AD. Specifically, we examined the effects of ceftriaxone in the okadaic acid (OKA)-induced AD model. In this model, intracerebroventricular (i.c.v.) OKA treatment leads to neuroinflammation, oxidative stress, cholinergic dysfunction, neuroinflammation, mitochondrial dysfunction, glutamate-mediated excitotoxicity, and impairments in learning and memory. Phosphorylation of tau protein and GSK3β and thereby formation of NFTs and extracellular β-amyloid deposits as well as the consecutive neuronal loss provide an AD like neuropathology in this model [15,16]. In this electrophysiological study, we have evaluated the long-term synaptic plasticity of neurons by measuring LTP, a long-lasting increase in synaptic strength, in hippocampal DG neurons. LTP has been proposed as a model responsible for consolidation of long-term memory with proposed molecular mechanisms which can provide the level of stability needed to maintain memories for months or longer. Therefore, we explored the effect of ceftriaxone on paired-pulse paradigm and long-term potentiation of hippocampal dentate gyrus (DG) neurons, which are involved in spatial pattern separation, together with the evaluation of short- and long-term memory in OKA-treated rats.
Section snippets
Animals and ethics
Male Wistar rats weighing 300–350 g maintained under standard housing conditions at an ambient temperature of 21–25 °C with food and water ad libitum. All experimental procedures were approved by the Ethics Committee of Ardabil University of Medical Sciences (GN-9423) and were performed in accordance with relevant guidelines and regulations.
Treatments
Animals were divided into four control (vehicle), ceftriaxone (CFT), OKA, and OKA plus ceftriaxone (OKA + CFT) groups (n = 10 in each group). OKA
Electrophysiology
In this study, the input-output (I/O) responses were assessed by delivering variety of stimulus current (0.1–1 μA) for evaluation of synaptic potency prior to LTP induction. The responses show the dependence of neural action potentials to excitatory input. Two-way mixed ANOVA indicated that the stimulus-response curves recorded from DG before the paired-pulse or high-frequency stimulations were not significantly different in fEPSP slope (F(3,24) = 0.32, p = 0.80) and PS amplitude
Discusstion
This study aimed to investigate whether treatment with ceftriaxone, a well-known upregulator of GLT-1, could ameliorate an AD-like impairment in behavior and synaptic plasticity in OKA-induced AD in rats. Application of β-lactam antibiotic ceftriaxone at a dose known to stimulate the expression of glial GLT-1 [23,24] significantly offset effects of OKA on behavior and electrophysiological activity of DG neurons. More specifically, i.c.v. injection of OKA alone significantly attenuated the
Declaration of competing interest
The authors have no conflicts of interest to declare.
Acknowledgments
This study was supported by a grant from Vice Chancellor of Research of Ardabil University of Medical Sciences (GN-9423).
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These authors contributed equally to this work.