Mechanisms Underlying The Enhanced Neural Excitation In The DG Area Of The Hippocampus Induced By Sodium Salicylate In Rats

Background:Sodium salicylate(NaSal),which belongs to the family of the non-steroidal anti-inflammatory drugs,is one of the Salicylates that are widely prescribed in the world.Besides anti-inflammatory,antipyretic,and antithrombotic properties,NaSal may have potential roles in decreasing the risk of certain cancers and Alzheimer's disease.However,NaSal also has undesirable effects.For example,NaSal can cause gastrointestinal irritation and hyperpyrexia.Previous investigations indicate that high doses of NaSal can lead to auditory sensory dysfunctions,such as temporary hearing loss and tinnitus,and can enhance sound-evoked responses and hyperactivity in the auditory-related areas such as the inferior colliculus,the medial geniculate body and the auditory cortex.As a matter of fact,NaSal imposes a wide range of effects on the central nervous systems.At present,the effects on and the mechanisms underlying the neural excitation following acute NaSal application,particularly in the hippocampus under an in vivo condition,is not fully understood.The aims of this study were to investigate the effects on and the mechanisms underlying the synaptic transmission in the PP-DG pathway and neural excitation in the hippocampal DG area in vivo following acute NaSal application.Methods:Field potential extracellular recordings in vivo and patch-clamp recordings were used in the present study.In the field potential recordings in vivo,we intraperitoneally injected rats with 50,150,250,350 mg/kg NaSal,respectively in the four NaSal groups,and injected rats with an equivalent volume of saline as a control group.We recorded field potentials and analyzed the field excitatory postsynaptic potential(fEPSP)and the population spike(PS)amplitude in the NaSal groups and in the control group to explore the effects of NaSal on the synaptic transmission and neural excitation in the hippocampal DG areas.Then we performed intrahippocampal micro injection to explore the mechanisms of NaSal underlying neural excitation.We inserted picrotoxin(PTX,a GABAA receptor antagonist)at 0.4 mM along the guide cannula of the recording electrode into DG areas before intraperitoneally administering rats with NaSal at a dose of 250 mg/kg to study the effects of NaSal on the fEPSP slope and the PS amplitude in the presence of PTX.In the patch-clamp recordings,we recorded and analyzed the evoked excitatory postsynaptic currents,the evoked inhibitory postsynaptic currents,the paired-pulse ratio in the PP-DG pathway,the miniature excitatory postsynaptic currents and the miniature inhibitory postsynaptic currents in the DG areas before and during the perfusion of 1 mM NaSal to further explore the mechanisms of NaSal underlying synaptic transmission and neural excitation.Results:(1)NaSal at various doses all significantly increased the fEPSP slope and PS amplitude,which indicates NaSal enhances synaptic transmission and neural excitation in the PP-DG pathway;(2)NaSal at 250 mg/kg increased the fEPSP slope and PS amplitude at various current intensities and led to leftward shifted E-S curve.This result demonstrates that NaSal enhances synaptic transmission and neural excitation;(3)NaSal at 250 mg/kg failed to increase the fEPSP slope and PS amplitude in the presence of PTX.This indicates that NaSal induces hyperactivity via reducing inhibitory synaptic transmission;(4)NaSal at 250 mg/kg affected neither the input/output curve nor E-S curve in the presence of PTX.This finding confirms that reduced GABAergic synaptic transmission contributes to NaSal-induced enhanced synaptic transmission and neural excitation;(5)In the hippocampal brain slices,NaSal significantly reduced the amplitude of evoked GABA receptor-mediated currents.However,NaSal affected neither the NMDA nor AMPA receptor-mediated currents.These results verify that NaSal enhances neural excitation through reducing GABAergic synaptic transmission;(6)NaSal decreased the amplitude of the first pulse and increased the paired-pulse ratio.This finding suggests a presynaptic mechanism involved in NaSal-induced reduction of the inhibitory synaptic transmission in the DG area;(7)NaSal decreased the frequency and amplitude of miniature inhibitory postsynaptic currents.This result provides evidence that postsynaptic mechanisms are associated with the reduction of inhibitory synaptic strength;(8)NaSal affected neither the frequency nor amplitude of miniature excitatory postsynaptic currents.This result suggests that the excitatory synaptic transmission may not be involved in the enhanced fEPSP slope by NaSal.