Longitudinal two-photon imaging in somatosensory cortex of behaving mice reveals dendritic spine formation enhancement by subchronic administration of low-dose ketamine

Abstract

Ketamine, a well-known anesthetic, has recently attracted renewed attention as a fast-acting antidepressant. A single dose of ketamine induces rapid synaptogenesis, which may underlie its antidepressant effect. To test whether repeated exposure to ketamine triggers sustained synaptogenesis, we administered a sub-anesthetic dose of ketamine (10 mg/kg i.p.) once-daily for 5 days, and repeatedly imaged dendritic spines of the YFP-expressing pyramidal neurons in somatosensory cortex of awake female mice using in vivo two-photon microscopy. We found that the spine formation rate became significantly higher at 72–132 h after the first ketamine injection (but not at 6–24 h), while the rate of elimination of pre-existing spines remained unchanged. In contrast to the net gain of spines observed in ketamine-treated mice, the vehicle-injected control mice exhibited a net loss typical for young-adult animals undergoing synapse pruning. Ketamine-induced spinogenesis was correlated with increased PSD-95 and phosphorylated actin, consistent with formation of new synapses. Moreover, structural synaptic plasticity caused by ketamine was paralleled by a significant improvement in the nest building behavioral assay. Taken together, our data show that subchronic low-dose ketamine induces a sustained shift towards spine formation.

The influence of ketamine’s repeated treatment on brain topology does not suggest an antidepressant efficacy

“…Conversely, the somato-motor cortical regions displayed strain-specific increased degree, strength and betweenness centrality. As degree and strength signify number and weights of connections, this change may rather reflect an increased dendritic spine formation in the somatosensory cortex, reported in mice treated for 5 days with 10 mg/kg ketamine 44 .…”

A pivot from synaptic monoamine processes to further downstream processes: The impact of ketamine research

“…9,11 These synaptic proteins produce an increase in dendritic spine density, and it is this proliferation of dendritic spines which is theorized to trigger the rapid antidepressant effect observed with ketamine administration. 13 Scientists have taken this thought one step further, however, and offered two theories describing how NMDA-receptor antagonism may result in the protein synthesis which is thought to stimulate synaptic activity in the corticolimbic structures. 14 One proposition is that these actions are achieved via selective antagonism in inhibitory interneurons, an action which then disinhibits cortical functions.…”

“…This available glutamate then binds to AMPA (A‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid) receptors, precipitating a signal transduction cascade, which in turn activates another pathway that results in synaptic protein synthesis . These synaptic proteins produce an increase in dendritic spine density, and it is this proliferation of dendritic spines which is theorized to trigger the rapid antidepressant effect observed with ketamine administration …”

Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea

“…Recent studies have shown that several signaling pathways play important roles in HC regeneration by inducing the proliferation and differentiation of SCs and Lg5+ progenitors. The up-regulation of canonical Wnt signaling induces the proliferation of sensory precursors in the postnatal mouse cochlea [3,4,[11][12][13][14][15][16][17], while Notch inhibition induces mitotic generation of HCs in the mammalian cochlea via activation of the Wnt pathway [12,14,[18][19][20][21][22][23][24][25]. Also, their effect on differentiation and the generation of HCs is related to important genes such as Atoh1 and Neurog1 [26][27][28][29][30][31][32][33][34].…”