Changes in cortical and hippocampal AMPA and NMDA receptors in post operative neuroinflammation

Abstract

Postoperative cognitive dysfunction (POCD) is common after surgery and has been described as a complication of cardiac surgery since the 1950s. It is more prevalent in the elderly and patients with preexisting neurocognitive disorders. Animal and human studies suggest that neuroinflammation from surgery and anesthesia is important in its development. Although the pathogenesis of POCD is still not clear, it may involve the central cholinergic system, the excitatory amino acid system, and other neurotransmitters. In this thesis, I used a murine surgical model that display postoperative learning and cognitive impairment as well as the release of proinflammatory cytokines increased after laparotomy surgery. Whole-cell patch-clamp electrophysiology was used to detect functional changes in neurotransmission. We found that surgery significantly increased the frequency of AMPAR-mediated miniature excitatory postsynaptic currents (mEPSCs) without altering mEPSC amplitudes in both the medial prefrontal cortex (mPFC) and hippocampus, with the increase in mEPSC frequency lasting at least 14 days in the mPFC. In the evoked excitatory postsynaptic currents (eEPSCs) experiment, I found a decreased paired-pulse ratio (PPR) after surgery that further verified an increase in the presynaptic release of glutamate neurotransmitters rather than an increase in postsynaptic receptor numbers. Moreover, I found that the NMDAR- mediated eEPSC currents increased compared to AMPAR-mediated eEPSC currents in the hippocampus after the surgery, combined with the increased expression of NR2B subunit in the frontal cortex and hippocampus, indicating an increased postsynaptic NMDAR number. However, the inhibitory neurotransmission mediated by GABAergic neurons was not significantly affected by surgery in both the mPFC and hippocampus. In contrast, surgery increased the inhibitory neurotransmission without altering the excitatory neurotransmission in the barrel cortex, indicating an excitation/inhibition (E/I) imbalance in different brain regions. I further found increased activity of the neural network in the mPFC and hippocampus by using multichannel recordings in vivo that showed an increase in synchronous activity in the prefrontal-hippocampus pathway. Two-photon imaging was then used to visualize AMPARs trafficking, and I observed an increase in AMPARs expression on the surface of dendrite spines both in young and old mice after the surgery. These results demonstrate a disturbance in the E/I balance and abnormal AMPARs trafficking in postoperative neuroinflammation.