Persistent blocking of NMDAR and burst-type firing by lateral habenula (LHb) neurons may offer a basis for the long-lasting antidepressant effects of ketamine.
By Pooja Toshniwal PahariaOct 22 2023Reviewed by Benedette Cuffari, M.Sc. In a recent study published in the journal Nature, researchers investigate whether persistent blocking of N-methyl-D-aspartate receptor and burst-type firing by lateral habenula neurons may offer a basis for the long-lasting antidepressant effects of an NMDAR agonist, ketamine.
This has important therapeutic significance, as ketamine inhibits NMDAR-dependent bursting activity in the LHb, which is a hallmark of neuronal activity in several animal models of depression. However, the mechanisms behind ketamine's long-lasting antidepressant effects are poorly known. Furthermore, its long-term effects are not only a fundamental biological concern but also have important therapeutic consequences.
AMPAR- and NMDAR-mediated excitatory postsynaptic currents were identified in LHb brain slices based on their temporal features and their input-output curves were investigated. Pure NMDAR-eEPSCs were isolated from the LHb of CRS animals using GABAAR blocker, picrotoxin, and the AMPAR blocker, NBQX, to validate the sustained NMDAR blocking effects of ketamine.
Study findings One systemic injection of ketamine suppressed burst-type firing in the lateral habenula by blocking NMDAR receptors for about 24 hours. This long-lasting NMDAR inhibition was related to the usage-based NMDA receptor trapping by ketamine and neural activity controlled the untrapping rate.
The burst-firing neuronal proportion remained much lower 24 hours following ketamine administration at 44% and 24% for saline- and ketamine-treated groups, respectively. The inhibition of LHb bursting activity was non-significant three days following ketamine administration.
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