Abstract
BackgroundGlutamatergic neurons represent the largest neuronal class in the brain and are responsible for the bulk of excitatory synaptic transmission and plasticity. Abnormalities in glutamatergic neurons are linked to several brain disorders and their modulation represents a potential opportunity for emerging bioelectronic medicine (BEM) approaches. Here, we have used a set of electrophysiological assays to identify the effect of the pyrimidine nucleoside uridine on glutamatergic systems in ex vivo brain slices. An improved understanding of glutamatergic synaptic transmission and plasticity, through this type of examination, is critical to the development of potential neuromodulation strategies.MethodsEx vivo hippocampal slices (400 μm thick) were prepared from mouse brain. We recorded field excitatory postsynaptic potentials (fEPSP) in the CA1’s stratum radiatum by stimulation of the CA3 Schaeffer collateral/commissural axons. Uridine was applied at concentrations (3, 30, 300 μM) representing the physiological range present in brain tissue. Synaptic function was studied with input-output (I-O) functions, as well as paired-pulse facilitation (PPF). Synaptic plasticity was studied by applying tetanic stimulation to induce post-tetanic potentiation (PTP), short-term potentiation (STP) and long-term potentiation (LTP). Additionally, we determined whether uridine affected synaptic responses carried solely by n-methyl-d-aspartate receptors (NMDARs), particularly during the oxygen-glucose deprivation (OGD) paradigm.ResultsThe presence of uridine altered glutamatergic synaptic transmission and plasticity. We found that uridine affected STP and LTP in a concentration-dependent manner. Low-dose uridine (3 μM) had no effect, but higher doses (30 and 300 μM) impaired STP and LTP. Moreover, uridine (300 μM) decreased NMDAR-mediated synaptic responses. Conversely, uridine (at all concentrations tested) had a negligible effect on PPF and basal synaptic transmission, which is mediated primarily by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). In addition, uridine (100 μM) exerted a protective effect when the hippocampal slices were challenged with OGD, a widely used model of cerebral ischemia.ConclusionsUsing a wide set of electrophysiological assays, we identify that uridine interacts with glutamatergic neurons to alter NMDAR-mediated responses, impair synaptic STP and LTP in a dose-dependent manner, and has a protective effect against OGD insult. This work outlines a strategy to identify deficits in glutamatergic mechanisms for signaling and plasticity that may be critical for targeting these same systems with BEM device-based approaches. To improve the efficacy of potential neuromodulation approaches for treating brain dysfunction, we need to improve our understanding of glutamatergic systems in the brain, including the effects of modulators such as uridine.
Highlights
Glutamatergic neurons represent the largest neuronal class in the brain and are responsible for the bulk of excitatory synaptic transmission and plasticity
Using a wide set of electrophysiological assays, we identify that uridine interacts with glutamatergic neurons to alter n-methyl-d-aspartate receptors (NMDARs)-mediated responses, impair synaptic short-term potentiation (STP) and long-term potentiation (LTP) in a dose-dependent manner, and has a protective effect against oxygenglucose deprivation (OGD) insult
To improve the efficacy of potential neuromodulation approaches for treating brain dysfunction, we need to improve our understanding of glutamatergic systems in the brain, including the effects of modulators such as uridine
Summary
Glutamatergic neurons represent the largest neuronal class in the brain and are responsible for the bulk of excitatory synaptic transmission and plasticity. Abnormalities in glutamatergic neurons are linked to several brain disorders and their modulation represents a potential opportunity for emerging bioelectronic medicine (BEM) approaches. The current approaches have mainly focused on electrical stimulation of the peripheral nervous system, but there is potential of employing the principles of synaptic function, synaptic plasticity, and brain biochemistry for the implementation of bioelectronic approaches in the CNS. There are three classes of ionotropic glutamate receptors, namely NMDARs, AMPARs and kainate receptors, which have a role not just in excitatory synaptic transmission and in synaptic plasticity and higher cognitive functions. We aimed to investigate whether uridine is capable of altering glutamatergic synaptic transmission and synaptic plasticity with the use of ex vivo hippocampal slices and electrophysiological recordings. It has been shown that brain slices subjected to a brief OGD injury exhibit regionally selective death of pyramidal neurons in the CA1 region, and have been used to model different brain disorders (Cho et al, 2007)
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