Elsevier

Life Sciences

Volume 238, 1 December 2019, 116969
Life Sciences

Effect of ceftriaxone on paired-pulse response and long-term potentiation of hippocampal dentate gyrus neurons in rats with Alzheimer-like disease

https://doi.org/10.1016/j.lfs.2019.116969Get rights and content

Abstract

Aims

Glutamatergic dysfunction is posed as a main stage in neurodegenerative disorders such as Alzheimer's disease (AD). Glutamate-mediated excitotoxicity contributes to cognitive dysfunction and cell death in AD. Ceftriaxone (CFT), a well-known upregulator of GLT-1, selectively induces the expression of glutamate transporter-1 (GLT-1) in different brain regions and therefore can be posed as a potential candidate for elimination of glutamate-induced excitotoxicity which is an early prominent event in AD brains. This study was designed to investigate the electrophysiological and behavioral effects of the β-lactam antibiotic ceftriaxone in okadaic acid (OKA)-induced model of AD.

Materials and methods

Male Wistar rats divided into four control, ceftriaxone (CFT), OKA, and OKA plus ceftriaxone (OKA + CFT) groups. OKA was injected intracerebroventricularly (i.c.v., 200 ng/5 μl) into lateral ventricles and after two weeks the evoked field potential recorded from hippocampal perforant path-DG synapses in order to evaluate the effect of ceftriaxone treatment (200 mg/kg/day, i.p.) on long-term potentiation (LTP) and paired-pulse responses.

Key findings

Results of this study revealed that ceftriaxone treatment significantly ameliorates the OKA-induced attenuation of field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude following high-frequency stimulation and paired-pulse paradigm indicating its beneficial effects on both short-term and long-term plasticity in these neurons. Ceftriaxone also has an improving effect on OKA-induced impairment in short- and long-term memories evaluated by alternation behavior and passive avoidance tasks in rats.

Significance

Therefore, this study suggests that GLT-1 might be a promising therapeutic target for treatment of neurodegenerative disorders such as AD in the future.

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).

References (54)

  • S.P. Braithwaite et al.

    Protein phosphatases and Alzheimer's disease

    Prog. Mol. Biol. Transl. Sci.

    (2012)
  • P.K. Kamat et al.

    Okadaic acid (ICV) induced memory impairment in rats: a suitable experimental model to test anti-dementia activity

    Brain Res.

    (2010)
  • P.K. Kamat et al.

    Mechanism of synapse redox stress in okadaic acid (ICV) induced memory impairment: role of NMDA receptor

    Neurochem. Int.

    (2014)
  • N. Broetto et al.

    Intracerebroventricular administration of okadaic acid induces hippocampal glucose uptake dysfunction and tau phosphorylation

    Brain Res. Bull.

    (2016)
  • P.K. Kamat et al.

    Okadaic acid-induced Tau phosphorylation in rat brain: role of NMDA receptor

    Neuroscience

    (2013)
  • S.K. Hota et al.

    Ceftriaxone rescues hippocampal neurons from excitotoxicity and enhances memory retrieval in chronic hypobaric hypoxia

    Neurobiol. Learn. Mem.

    (2008)
  • S.-C. Ho et al.

    Effects of ceftriaxone on the behavioral and neuronal changes in an MPTP-induced Parkinson's disease rat model

    Behav. Brain Res.

    (2014)
  • C. Carvalho et al.

    Alzheimer's disease and type 2 diabetes-related alterations in brain mitochondria, autophagy and synaptic markers

    Biochim. Biophys. Acta (BBA) - Mol. Basis Dis.

    (2015)
  • J. Zumkehr et al.

    Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimer's disease

    Neurobiol. Aging

    (2015)
  • 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

    J. Biol. Chem.

    (2000)
  • F. Matos-Ocasio et al.

    Ceftriaxone, a GLT-1 transporter activator, disrupts hippocampal learning in rats

    Pharmacol. Biochem. Behav.

    (2014)
  • Y. Chen et al.

    Synaptic release rather than failure in the conditioning pulse results in paired-pulse facilitation during minimal synaptic stimulation in the rat hippocampal CA1 neurones

    Neurosci. Lett.

    (1996)
  • D. Fioravante et al.

    Short-term forms of presynaptic plasticity

    Curr. Opin. Neurobiol.

    (2011)
  • P.J. Yao

    Synaptic frailty and clathrin-mediated synaptic vesicle trafficking in Alzheimer's disease

    Trends Neurosci.

    (2004)
  • J. Lewerenz et al.

    Chronic glutamate toxicity in neurodegenerative diseases—what is the evidence?

    Front. Neurosci.

    (2015)
  • R. Cacabelos et al.

    The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease

    Int. J. Geriatr. Psychiatry

    (1999)
  • E.L. Schaeffer et al.

    Cholinergic and glutamatergic alterations beginning at the early stages of Alzheimer disease: participation of the phospholipase A 2 enzyme

    Psychopharmacology (Berl)

    (2008)
  • Cited by (19)

    • Zinc exacerbates tau-induced Alzheimer-like pathology in C57BL/6J mice

      2023, International Journal of Biological Macromolecules
    • Melatonin treatment improves cognitive deficits by altering inflammatory and neurotrophic factors in the hippocampus of obese mice

      2022, Physiology and Behavior
      Citation Excerpt :

      Obesity and cognitive impairment share common molecular and pathological mechanisms such as neuroinflammation, abnormal neurotrophic signaling, and hippocampal dysfunction [17,35,49,55,60,77]. The hippocampus is well recognized for its role in modulating working, spatial, and recognition memory [7,8,21,27,30,75]. Recent studies have identified that increased inflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-17 and decreased neurotrophin brain-derived neurotrophic factor (BDNF), particularly in the hippocampus, are associated with cognitive deficits [14,22,23,26,68,72,89,92].

    • The gut microbiome and adult hippocampal neurogenesis: A new focal point for epilepsy?

      2022, Neurobiology of Disease
      Citation Excerpt :

      Ex vivo hippocampal slice electrophysiological recordings revealed that although GF mice displayed normal basal synaptic excitability compared to conventional mice, a significant decrease was observed in long-term potentiation in GF mice, as detected by field excitatory postsynaptic potential (fEPSP) measures (Darch et al., 2021). Ceftriaxone treatment (a β-lactam antibiotic) has shown therapeutic potential by attenuating the exacerbated hippocampal fEPSP slope and population spike amplitude in the okadaic acid model of Alzheimer’s disease in the rat and by improving short- and long term memory assessed by alternating behaviour and passive avoidance tasks (Hamidi et al., 2019). It is worth noting that ceftriaxone has been associated with mechanisms linked to the excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes (Lee et al., 2008), so it remains unclear whether ceftriaxone effects in vivo are mediated by its antibiotic properties.

    • Early life GABA<inf>A</inf> blockade alters the synaptic plasticity and cognitive functions in male and female rats

      2022, European Journal of Pharmacology
      Citation Excerpt :

      Short-term spatial memory was evaluated by monitoring spontaneous alternation behavior in a black Plexiglas Y–maze (each arm 40 × 30 × 15 cm). The Y–maze experiment was performed as described previously (Hamidi et al., 2019a). The rat was placed in one of the arms and the movements through the maze were visually monitored for an 8-min session.

    • Neonatal NMDA blockade alters the LTP, LTD and cognitive functions in male and female Wistar rats

      2022, Neuropharmacology
      Citation Excerpt :

      The experiment details were the same as that described previously as follows: the rat was placed at one of the arms and the movements through the maze were monitored visually for an 8-min session. Complete entries into the three arms on overlapping triplet sets were considered as a successful alternation and the alternation behavior was calculated as the percentage of actual alternations (Hamidi et al., 2019a). After habituation in a light/dark chamber, rats were put in a light chamber for a training trial.

    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    View full text