Neuroplasticity is an important property of neuronal adaptation, which may be disrupted in depression (Manji et al. 2001; Manji et al. 2000). Neuroplasticity changes induced by external environmental factors, such as stress and other negative stimuli, have been demonstrated to play a significant role in both the onset and precipitation of depression (Pittenger and Duman 2008). Conversely, antidepressant intervention has been suggested to exert an important part of the antidepressant effects through regulation of neuroplasticity (Duman and Aghajanian 2012; Duman et al. 2016). It is believed that various neurotrophins, a family of small peptide growth factors, regulate neuroplasticity, which include proliferation, differentiation, survival and death of neuronal cells and supporting tissue (Levy et al. 2018). Brain-derived neurotrophic factor (BDNF), the predominant neurotrophin in the brain, binds to the tropomyosin receptor kinase B (TrkB) receptor and subsequently activates intracellular signalling pathways governing transcription and dendritic translation of proteins necessary for cellular survival, differentiation and learning/memory formation in the hippocampus (Leal et al. 2017). Importantly, dysfunctional signalling through BDNF and TrkB has been implicated in a number of psychiatric disorders, including depression (Autry and Monteggia 2012). In support of that, stress decreases whereas chronic treatment with antidepressants increases BDNF levels in the prefrontal cortex and in the hippocampus and intact BDNF signalling in the brain is shown to be necessary for the behavioural effects of conventional antidepressants (Adachi et al. 2008; Autry and Monteggia 2012).

Interestingly, NO seems to be also able to modulate BDNF levels, since it was demonstrated that NO donors (SNP, NOR3) decrease BDNF release in hippocampal cell culture, whereas the inhibition of NO production increases these levels (Canossa et al. 2002). Accordingly, in vivo experiments showed that chronic treatment with l-NAME increased BDNF mRNA and protein levels in the hippocampus and in the prefrontal cortex of rats (Pinnock and Herbert 2008; Salehpour et al. 2017). In line with this observation, the antidepressant-like effect induced by chronic treatment with the selective nNOS inhibitor 7-NI or with the sGC inhibitor ODQ was associated with increased expression of hippocampal BDNF protein levels (Stanquini et al. 2018). Similarly, increased levels of BDNF have also been observed after treatment with other NOS inhibitors, either in cultured or in vivo neocortex (Xiong et al. 1999). However, in another study, the antidepressant effect induced by aminoguanidine, a preferential iNOS inhibitor, was not correlated with increased BDNF signalling in the prefrontal cortex of FSL rats (Silva Pereira et al. 2017). Mice with deficient iNOS expression, however, present increased BDNF levels in the PFC and hippocampus associated to antidepressant-like phenotype (Joca et al. 2012). It is, therefore, likely that both iNOS- and nNOS-derived NO can modulate BDNF signalling in stress adaptation. Although NO has usually been shown to downregulate BDNF levels, peroxynitrite formation derived from NO and O2− was observed to trigger TrkB signalling (Yuen et al. 2000), suggesting BDNF signalling to be affected. Evidence from cultured hippocampal neurons indicates that inhibition of BDNF secretions is more pronounced in response to exogenous NO levels or under exacerbated NO concentrations, whereas endogenous low levels of NO would facilitate BDNF–TrkB signalling (Kolarow et al. 2014). A bioinformatic analysis predicted a direct action of NO on the amino acid residues of BDNF or TrkB, suggesting protein S-nitrosylation or tyrosine nitration in both rodents and humans quoted molecules (Biojone et al. 2015). These direct actions of NO on BDNF or TrkB proteins could trigger functional negative feedback to control protein function, or it could drive a reinforcement of downstream BDNF/trkB signalling.

Conversely, neurotrophins are also able to modulate NO or NOS levels, since BDNF has been found to upregulate NO signals, in either hippocampal or neocortical neurons (Kolarow et al. 2014; Xiong et al. 1999). Similarly, the ratio of nNOS-positive neural progenitor cells (NPCs) is increased following treatment with BDNF (Cheng et al. 2003). On the other hand, BDNF can suppress NO production in microglia, thus counteracting inflammatory processes in the brain (Mizoguchi et al. 2014).

More recent evidence indicated that the interplay between NO and BDNF-TrkB signalling is more complex and involves more signalling cascades. Both NMDA and TrkB can be associated to PSD-95 and induce downstream signalling mechanisms that regulate synaptic plasticity (Cai et al. 2018). In this scenario, PSD-95–nNOS interaction may downregulate BDNF expression via inhibiting ERK activation. On the other hand, NMDA–PSD-95 uncoupling would increase BDNF levels and facilitate BDNF–TrkB–PSD-95 signalling mechanisms related to neuroplasticity, which could contribute to the behavioural effect of these drugs. These results could help explain the effect of NOS inhibitors on BDNF expression.

In humans, a recent study conducted with patients presenting elevated depressive symptoms revealed decreased serum BDNF levels associated to increase NO levels and impaired antioxidant capacity (Eraldemir et al. 2015). Although it is not possible to infer about brain NO and BDNF levels in these patients, studies conducted with brain tissue from animal’s have given further support for a putative role of NO in regulating BDNF levels under stressful situations and depression.

Despite the aforementioned evidence that NO might regulate BDNF levels in stress and depression, evidence about the effects of NOS inhibitors in promoting recovery of impaired synaptogenesis and dendritic branching in stressed animals is scarce. It is known, however, that NO is critically involved in the establishment and activity-dependent refinement of axonal projections during the later stages of development (Manucha 2017). Under physiological concentrations, NO signals downstream, either through sGC activation or through nitrosylation to promote the growth of presynaptic filopodia, which rapidly leads to the formation of new synaptic contacts in in vitro experiments (Sunico et al. 2005). Conversely, high levels of NO, as in nerve injuries, can produce the opposite effect, with reduced synaptogenesis through cGMP-dependent and S-nitrosylation-mediated mechanisms (Sunico et al. 2005). Although this can be blocked by treatment with NOS inhibitors (Sunico et al. 2005) and since inhibition of NO synthesis in adult rats increases hippocampal expression of synaptophysin (Joca et al. 2007), it is not known whether blocking NO synthesis may prevent a stress-induced decrease in synaptogenesis and dendritic arboring. However, this seems likely, since PSD-95 promotes synaptogenesis and multi-innervated spine formation through nitric oxide signalling (Nikonenko et al. 2008). However, further research is needed and the question is open for investigation. A proper answer would contribute for a better understanding on the role of NO on stress-induced neuroplasticity related to neuropsychiatric disorders.

Another important neuroplasticy factor affected by NOS inhibitors is neurogenesis, which has been exhaustively reviewed elsewhere (Chong et al. 2018; Gray and Cheung 2014). Only a brief overview is presented here. Neurogenesis is the process of neural stem cells (NSCs) to foster newborn neurons in replacement for damaged neurons or maintaining the function. Neurogenesis has attracted significant interest and although somewhat controversial in humans, it has been suggested that neurogenesis may be linked to recovery from clinical depression (Duman et al. 2001a; Duman et al. 2001b; Spalding et al. 2013) and even in a controversial paper that it may be a prerequisite for an antidepressant response (Santarelli et al. 2003). In the brain, neurogenesis has been observed in the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus (DG) (Ehninger and Kempermann 2008; Spalding et al. 2013). Interestingly, it has also been demonstrated that the subventricular zone is surrounded by nNOS positive neurons (Romero-Grimaldi et al. 2008) and cells expressing nNOS have also been identified in neuronal precursors in DG (Islam et al. 2003), suggesting that nNOS could participate in the regulation of neurogenesis. Indeed, it has been demonstrated that the nNOS-mediated suppressing on neurogenesis effect may be caused by NO generated from neurons, not from NSCs (Luo et al. 2010). In addition, evidence that the subcellular localizations of nNOS in neurons and in NSCs seems to be distinct, implying that the role of nNOS in neurons and NSCs is different (Luo et al. 2010). It has also been demonstrated that inhibition of NO synthesis with 7-NI increases proliferation of neural precursors isolated from the postnatal mouse subventricular zone (Matarredona et al. 2004). However, another report has demonstrated that nNOS inhibition with 7-NI enhanced the proliferation of progenitor cells in the dentate gyrus and that the antidepressant-like effect of this drug was dependent on this neurogenic effect (Zhu et al. 2006). These results are in line with findings using a nNOS knockout mouse line, where the number of new cells, generated in neurogenic areas of the adult brain, the olfactory subependyma and the dentate gyrus, was strongly augmented, indicating that division of neural stem cells in the adult brain can be negatively controlled by NO (Packer et al. 2003). It has also been reported that the nNOS inhibitor l-VNIO or deletion of the nNOS gene could affect the differentiation of NSCs into neurons and astrocytes (Luo et al. 2010). Specifically, it was found that nNOS could facilitate differentiation of hippocampal neural progenitor cells (Park et al. 2017), suggesting that nNOS in NSCs is essential for neurogenesis. In the DG of the hippocampus, NSC forms granule neurons contributing to neuroplasticity, learning and memory. Impairments in these cognitive functions have been observed in nNOS transgenic mice, suggesting that nNOS affects differentiation of NSCs in the DG (Weitzdoerfer et al. 2004). High levels of the nNOS are found in granule neurons in the DG (Islam et al. 2003) and NO generated from nNOS in these neurons may therefore be speculated to negatively govern granule neuronal precursor proliferation and further reduces differentiation of granule neuronal precursors. Given these observations, it is possible to speculate that the behavioural effects of NOS inhibitors observed in animals under exposure to chronic stress might involve positive regulation of hippocampal neurogenesis.

One of the special physiological properties of NO is the function as a retrograde messenger, influencing synaptic properties, such as LTP and LTD (Izumi and Zorumski 1993; Zorumski and Izumi 1993). Such processes are crucial in synaptic homeostasis and, conversely, affecting NO levels may virtually affect the plasticity and homeostasis of all known synapses (Hardingham et al. 2013; Hölscher 1997). In diseases where synaptic dysfunction, such as depression, is important, NO is likely to play a major role. In fact, NO has been shown to mediate local activity-dependent excitatory synapse development and spine dynamics (Nikonenko et al. 2013) and a change in NO levels during development has been shown to promote axon pruning in a cGMP-independent mechanism and to enable a switch between phases of neuronal degeneration and regrowth (Rabinovich et al. 2016).

Changes in synaptic function are similarly reflected in the observed levels of neurotransmitters. Several in vivo studies have demonstrated that NO can modulate the extracellular level of neurotransmitters in the central nervous system, e.g., 5-HT, DA, GABA and glutamate (Kaehler et al. 1999; Lorrain and Hull 1993; Segovia et al. 1997; Segovia et al. 1999; Segovia et al. 1994; Strasser et al. 1994; Wegener et al. 2000). In addition, NO can inactivate the rate limiting enzyme in the synthesis of 5-HT, tryptophan hydroxylase (Kuhn and Arthur Jr. 1996, 1997) and it has been suggested to stimulate synaptic vesicle release from hippocampal synaptosomes (Meffert et al. 1996; Meffert et al. 1994). Furthermore, NO regulates 5-HT reuptake (Pogun et al. 1994a; Pogun et al. 1994b; Pogun and Kuhar 1994), inhibits uptake of [3H] DA by striatal synaptosomes (Lonart et al. 1993; Lonart and Johnson 1994) and transforms 5-HT into an inactive form (Fossier et al. 1999). It has also been demonstrated that a physical interaction between the serotonin transporter and neuronal nitric oxide synthase, via PDZ-PDZ interactions, may underlie reciprocal modulation of their activity (Chanrion et al. 2007). The connection between NO and 5-HT is substantiated by observations showing that NO as well as 5-HT are involved in the pathophysiology of migraine (Lassen et al. 1998; Lassen et al. 1997; Thomsen 1997; Thomsen and Olesen 1998), as well as the inverse relationship between NO and 5-HT in peripheral tissue. These neurochemical studies could provide evidence for the observation that the antidepressant-like effect induced by NOS inhibitors is dependent on brain serotonin levels.