To further investigate the relationship between the pro neur

To further investigate the relationship between the pro-neurogenic and therapeutic actions, we analyzed the effect of VP2.51 in the presence of the antimitotic agent TMZ. No overt side effects were found at the time of testing as assessed by direct observation of the behavior of the animals in their cage, but only a slight weight loss. This drug was used according to previously published protocols for the reduction of adult hippocampal neurogenesis (Garthe et al., 2009; Castilla-Ortega et al., 2016). Since the VP2.51 effect is abolished in the TMZ + VP2.51 treated animals, we conclude that AHN is mediating the antidepressant effects of VP2.51. Currently there is a considerable controversy as to whether AHN is a necessary mediator of antidepressant interventions. While AHN appears to be fundamental for the antidepressant and anxiolytic effects of several interventions (David et al., 2009, Mateus-Pinheiro et al., 2013), elsewhere it did not appear to be necessary to elicit the anxiolytic and spatial learning effects of environmental enrichment (Meshi et al., 2006) or of some antidepressant drugs (Bessa et al., 2009). However, to increase AHN alone was recently described as sufficient to decrease anxiety and depression-like behavior in a mouse model of stress (Hill et al., 2015). While further studies will be needed to fully define the mechanisms underlying the antidepressant effects of certain therapies, adult hippocampal neurogenesis is undoubtedly related to these mechanisms (Eisch and Petrik, 2012), and our results add further support to the neurogenic hypothesis of depression. Together, such evidence clearly indicates that the antidepressant effects related to the GSK-3β pathway involve AHN.
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Conflict of interest
Acknowledgements This work was supported by grants from the Ministerio de Ciencia e Innovación (BFU2007-60195 JLT) and Ministerio de Economía y Competitividad (BFU2013-48907-R JLT and SAF2012-37979-C03-01 AM), CIBERNED and Madrid Council (P2010/BMD-2349-MLC). We thank Belén García and Carmen Hernández for their help with the confocal microscopy, and Ainhoa Arias from the Behavioral Unit and Laude Garmendia for their help with the animals (all at the Cajal Institute). We thank Dr Mark Sefton, and Kerry R. McGreevy for English edition of the manuscript. PPD held a CIBERNED contract. The authors disclose any conflict of interest that could be perceived to bias their work.
GSK-3 in the CNS The first indication that glycogen synthase kinase-3 (GSK3) plays a role in the Hydrochlorothiazide synthesis emerged from the demonstration that the ‘classical’ mood stabilizer lithium inhibits GSK-3 [1], [2]. This unexpected finding made GSK-3 the subject of considerable research in the psychiatric arena; however, as alterations in mood behavior are tightly coupled with neurological disorders, efforts soon shifted toward attempts to understand GSK-3 signaling in the CNS. Numerous studies have now implicated GSK-3 in control of various neuronal functions and have demonstrated that aberrant regulation of GSK-3 is involved in the etiology of neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, and Alzheimer's disease (AD), as well as in brain aging [3], [4], [5], [6], [7], [8]. Transgenic mice expressing elevated GSK-3 activity display memory deficits, reduced brain size and alterations in mood behavior and social interactions [9], [10], [11], [12]. These animals also developed characteristics of AD such as hyper-phosphorylation of the microtubule associated protein tau and beta-amyloidal aggregates [13], [14], [15], [16]. Pharmacological inhibitors or selective GSK-3 knockout models also demonstrated the impact of this kinase on brain morphology, neuronal plasticity and behavior [17], [18], [19], [20], [21], [22], [23]. Abnormal regulation of GSK-3 activity is reported in patients with AD, ALS, major depression, schizophrenia and bipolar disorder [12], [24], [25], [26], [27], [28], [29], [30], [31]. The mechanisms linking GSK-3 with pathogenesis likely involve regulation of targets that are directly or indirectly controlled by GSK-3. These include the microtubule associated protein tau, presenilins, amyloid precursor protein, collapsin response mediator proteins, components of the Wnt signaling pathway, β-catenin, and heat shock proteins [3], [4], [5], [6] (Table 1). It is also noteworthy that GSK-3 contributes to inflammatory processes that have been recently recognized as important elements in neurodegenerative disorders. GSK-3 likely activates a variety of immune response targets, such as toll-like receptors, transcription factor NF-κB, cyclic-AMP response element binding protein, and proteins involved in cytokine production [32], [33] (Table 1). Finally, GSK-3 has recently emerged as a negative regulator of lysosomes, which results with reduction in clearance efficiency of intracellular neurotoxic aggregates, such as Aβ depositions in the AD brain [34], [35]. Thus, ‘normalization’ of GSK-3 activity emerges as a promising therapy for treatment of neurodegenerative and behavior disorders. Indeed, inhibition of GSK-3 results in beneficial outcomes in multiple in vivo models (Table 1).