Effects of ketamine on dendritic spine plasticity in a mouse restraint stress model : involvement of parvalbumin interneurons

Abstract

In patients of major depressive disorder, structural and functional deficits are reported in the prefrontal cortex (PFC). In rodent models of depression, chronic stress significantly reduced the density of dendritic spines, the major input site of excitatory synapses, in pyramidal neurons from the PFC. Ketamine, a N-methyl-D-aspartate receptor (NMDAR) antagonist, was found to exert rapid antidepressant effect at a single, low dose in clinical and animal studies, as well as increasing dendritic spine density and enhancing excitatory synaptic transmission in rodent PFC. Emerging evidences suggest that structural modification of dendritic spines by ketamine is critical for its antidepressant effect. Nevertheless, dendritic spines are highly dynamic structures, and the effect of ketamine on the structural plasticity of dendritic spines in a depression-related context is unknown. The ‘disinhibition hypothesis’ proposes that ketamine augments excitatory synaptic transmission by suppressing inhibitory interneurons. This is based on the observation that NMDAR antagonist preferentially decreased the activity of fast-spiking interneurons and caused a delayed increase in pyramidal neuron activity in rodent PFC. The major potential target of ketamine is parvalbumin (PV)- expressing interneurons, which are fast-spiking and the largest subpopulation of cortical interneurons. Nevertheless, the effect of ketamine on PV interneurons and the role of PV interneurons in the action of ketamine remain elusive.

In the present study, the effect of ketamine on dendritic spine plasticity in the frontal association cortex (FrA) of repeatedly restraint stressed mice was studied using longitudinal in vivo transcranial imaging. The result showed a single, low dose of ketamine counteracted stress-induced elimination of mushroom spines, and repeated doses are required for sustained effect. In non-stressed mice, ketamine transiently increased spine formation rate and did not affect spine elimination, suggesting the effect of ketamine on spine elimination is stress-specific. On the other hand, ketamine did not change the number of PV immunoreactive cells in the FrA of stressed mice. Instead, longitudinal in vivo cranial window imaging showed ketamine counteracted stress-induced loss of PV axonal boutons by enhancing PV bouton formation. In addition, data from ex vivo electrophysiological and in vivo functional calcium imaging experiments showed that low dose ketamine increased the activity of PV interneurons in FrA of stressed mice. Furthermore, chemogenetic manipulation of PV interneurons was performed to investigate the involvement of PV interneurons in ketamine’s action. The result showed that selective activation of PV interneurons in the FrA mimicked the protective effect of ketamine on mushroom spines and the anxiety-relieving effect of ketamine in stressed mice, whereas selective inhibition of PV interneurons abolished both effects.

In summary, the present study displayed how ketamine modulated dendritic spine plasticity in a mouse repeated stress model, and demonstrated for the first-time ketamine enhanced the structure and function of PV interneurons in stressed mice. This study also showed modulation of dendritic spines and behavioural effect of ketamine required activity of PV interneurons, suggesting a potential role of PV interneurons in the antidepressant action of ketamine.