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The novel antidepressant ketamine enhances dentate gyrus proliferation with no effects on synaptic plasticity or hippocampal function in depressive-like rats

Journal article
Authors Henrik Michaëlsson
Mats Andersson
Johan Svensson
Lars O Karlsson
Johan Ehn
Georgia Culley
Anders Engström
Nicklas Bergström
Parthenia Savvidi
Hans-Georg Kuhn
Eric Hanse
Henrik Seth
Published in Acta Physiologica
Volume 225
Issue 4
ISSN 1748-1708
Publication year 2019
Published at Institute of Neuroscience and Physiology
Language en
Links dx.doi.org/10.1111/apha.13211
Keywords AMPA, glutamatergic, neurogenesis, NMDA, silent synapses, stress-induced anhedonia, nmda receptor blockade, septo-temporal axis, rapid antidepressant, neonatal dexamethasone, ampa receptors, global, burden, protein-synthesis, mammalian target, prenatal stress, Physiology
Subject categories Neurosciences

Abstract

Aim Major depressive disorder is a common and debilitating condition with substantial economic impact. Treatment options, although effective, are aimed at relieving the symptoms with limited disease modification. Ketamine, a commonly used anaesthetic, has received substantial attention as it shows rapid antidepressant effects clinically. We studied the effects of ketamine on hippocampal function and dentate gyrus proliferation in rats showing a depressive-like phenotype. Methods Adolescent and adult animals were pre-natally exposed to the glucocorticoid analog dexamethasone, and we verified a depressive-like phenotype using behavioural tests, such as the sucrose preference. We subsequently studied the effects of ketamine on hippocampal synaptic transmission, plasticity and dentate gyrus proliferation. In addition, we measured hippocampal glutamate receptor expression. We also tested the ketamine metabolite hydroxynorketamine for NMDA-receptor independent effects. Results Surprisingly, our extensive experimental survey revealed limited effects of ketamine or its metabolite on hippocampal function in control as well as depressive-like animals. We found no effects on synaptic efficacy or induction of long-term potentiation in adolescent and adult animals. Also there was no difference when comparing the dorsal and ventral hippocampus. Importantly, however, ketamine 24 hours prior to experimentation significantly increased the dentate gyrus proliferation, as revealed by Ki-67 immunostaining, in the depressive-like phenotype. Conclusion We find limited effects of ketamine on hippocampal glutamatergic transmission. Instead, alterations in dentate gyrus proliferation could explain the antidepressant effects of ketamine.

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