Abstract
Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity. Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Ketamine reduced, while CP-101606 and Ro 25-6981 did not alter the LTP response. The administration of CP-101606 before TBS did not influence the effects of ketamine when administered half an hour after tetanization, suggesting a limited contribution of the NR2B subunit in the action of ketamine. This work confirms the role of NMDAR in the LTP form of synaptic plasticity, whereas specific blockade of the NR2B subunit was not sufficient to modify hippocampal LTP. Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model.
Highlights
The NMDA receptor acts as an activitydependent coincidence detector in the central nervous system (CNS), which is commonly identified with the induction of two forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), the dominant experimental models of synaptic plasticity and learning [5,6,10,11,12,13]
I/O curves that were generated before the LTP induction protocol were used as the first gate to establish inclusion and exclusion criteria
Compared to the in vivo LTP results, this study demonstrated the important balance between the possible effect and the side effects of CP-101606 and required an adequate therapeutic balance concerning the benefit/risk ratio [96]
Summary
There are four NR2 subunits (A–D) in the brain [15], while NR2A, NR2B and some NR1 are the central NMDAR subunits expressed in the brain of rodents These majorities of NMDAR subunits mainly ensure the association of the NR1–NR2A and NR1–NR2B complexes as heteromeric NMDARs at the synaptic level [4,16,17,18]. The NR2B and NR2A subunits are structurally and functionally distinct, providing properties unique to NMDAR function in transmission and basal synaptic plasticity. These two NMDAR subunits are expressed at different times of development: GluN2B is predominant in early postnatal development [19], while GluN2A levels gradually increase during development and exceed those of GluN2B [20,21,22]. NMDARs containing NR2B preferentially target extrasynaptic sites, while NMDARs containing NR2A are localized at the postsynaptic density [23]
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