In adult mice, FLX treatment converts differentiated DG neurons to a moreimmature state [
6‐
9]. Similar changes in DG neurons have been demonstrated in αCaMKIIHKO [
11], Shn-2 KO [
18], and SNAP-25 KI mice [
19]; this phenomenon has been termed the “immature DG” [
10]. In this study, we demonstrate for the first time that FLX treatmentmight also induce dematuration of parvalbumin+ interneurons in the mFC andhippocampal CA3 region, while our finding in the amygdala is consistent withthat of a previous study [
20]. Consistently, the present study demonstrates that chronic FLXtreatment increases the expression of polysialic acid-neural cell adhesionmolecule (PSA-NCAM), which is a marker for immature neurons and a regulator ofneural plasticity [
42,
43], in the mFC, hippocampus, and amygdala; this is in agreement withprevious findings [
44,
45] (Additional file
1: Figure S7). Thissuggests that dematuration of parvalbumin+ interneurons is induced by FLXtreatment in the mFC, hippocampus, and amygdala, where neural plasticity mightbe enhanced by FLX treatment. In line with this, FLX treatment has been reportedto reinstate neural plasticity and promote the electrophysiological andbehavioral recovery of functions in the visual cortex of adult amblyopic rats [
46]. In contrast, accelerated maturation of parvalbumin+ cells viaoverexpression of the neurotrophin brain-derived neurotrophic factor leads to areduced capacity for cortical neural plasticity [
47,
48]. Thus, dematuration of parvalbumin+ interneurons in the mFC,hippocampus, and amygdala might reinstate synaptic plasticity that is reducedwith age and development, thereby potentially causing the antidepressant effectof FLX. Further studies are required to address the causal relationship betweendematuration of parvalbumin+ cells and enhanced neural plasticity.
Recent findings have led to the hypothesis that problems in informationprocessing within neural networks, rather than altered chemical balance, mayaccount for the mechanism underlying depression [
49,
50]. Thus, antidepressant drugs may induce changes in neuronal morphologyand connectivity, gradually improving neuronal information processing andrecovering mood. Indeed, volume changes in the hippocampus, mPFC, or amygdalaare found both in patients with depression and in animal models of depression [
51,
52]. Previous studies, as well as the present one, have identified someof the effects of FLX on the brain, which include increased adult neurogenesisin the DG [
2] and cortex [
5], decreased adult neurogenesis in the SVZ [
6], dematuration of neurons in the DG [
7], amygdala [
20], and mFC. Most events occur in the FC and limbic system.Interestingly, it has become increasingly clear that network dysfunction in thePFC and limbic system, including the hippocampus and amygdala, is involved inthe pathophysiology of depressive disorder [
24,
53,
54]. Therefore, neuronal dematuration and adult neurogenesis in theseregions may play important roles in the mechanism of action of antidepressantdrugs like FLX. In addition, some of the adverse effects of FLX [
55], such as aggression, violence, and psychosis, might be mediated bythe dematuration of fast-spiking inhibitory interneurons in the mFC. Aggressionand violence are associated with deficits in the prefrontal cortex of humans [
56,
57], where activation of GABAergic interneurons decreases [
57]. Dematuration of fast-spiking inhibitory interneurons might decreaseinhibitory transmission of the interneurons, which in turn could evokeaggression and violence. It should be noted that, in post-mortem brains ofpatients with schizophrenia, the number of parvalbumin+ interneurons [
41,
58] and PNN+ cells [
59] is decreased in the prefrontal cortex. This dematuration ofparvalbumin+ fast-spiking interneurons by FLX treatment may be related tothe antidepressant-induced psychosis and agression observed in clinical settings [
55,
60]. Future studies will need to address the behavioral significance ofthe FLX-induced dematuration effect on fast-spiking inhibitory interneurons inthe mFC.