Theta rhythm stimulation patterns can reverse aberrant hippocampal CA1 synaptic plasticity under challenging conditions: Involvement of extracellular adenosine

In this study, experiments were conducted to investigate how primed theta-burst (PBs) and a theta pulse (TPS; 5 Hz trains for 3 min) stimulation along with pentylenetetrazol (PTZ) induced seizure like activity modulate long-term potentiation (LTP) in CA1 field recordings and whether extracellular adenosine plays a role in this modulation. Population spike (PS) was significantly enhanced for at least 1 h by short-term PTZ exposure (3 mM, 10 min), whereas the slope of the field excitatory postsynaptic potential (fEPSP) was not altered. PBs alone or in combination with short-term PTZ exposure induced LTP in fEPSP slope and PS amplitude. TPS was applied 3 min after PBs and 7 min after short-term PTZ exposure or PBs + PTZ, caused an immediate attenuation of the potentiated synaptic responses. TPS was applied 30 min after PBs or PTZ washout in the presence of EHNA (10 µM), an adenosine deaminase (ADA) inhibitor, had no effect on potentiated synaptic responses. Interestingly, when TPS was applied 30 min after PBs + PTZ, it was found that TPS-induced depotentiation was suppressed in the presence of ADA inhibitor. This effect was blocked by the adenosine A1 receptor (A1R) antagonist, CPX (200 nM). We showed that abnormal LTP induced under epileptogenic conditions can be modulated by theta-patterned stimulation and that ADA inhibition and A1R blockade alter the ability of such stimulation to induce depotentiation. These findings suggest involvement of extracellular adenosine in the regulating of aberrant synaptic plasticity, which could have implications for understanding hippocampal dysfunction associated with epileptic activity.