Abstract:
Neuropsychiatric disorders represent a significant global health burden. Despite decades of research, current treatments typically provide only symptomatic relief, rather than addressing the underlying mechanisms of these conditions. Historically, research focused on the dopaminergic and serotonergic systems, which are deeply involved in the pathophysiology of many mental health disorders, including depression, schizophrenia, anxiety, autism spectrum disorder (ASD), and different substance use disorders, including alcohol use disorder (AUD). However, therapies targeting these systems have limitations, often only producing partial symptom relief plus compliance-limiting side effects. This highlights the need for improved treatments that may emerge from a broader understanding of the neurobiological bases of these conditions, especially neurochemical systems beyond dopamine and serotonin. Additional monoamines (e.g., histamine, acetylcholine, norepinephrine), neurolipid systems (e.g., endocannabinoids), and diverse signaling molecules such as neuropeptides, trace amines, and cytokines are increasingly recognized as key players in the dysfunction of neural circuits. In this review, which originated from the International Society for Neurochemistry (ISN)/Journal of Neurochemistry 5th Flagship School in October 2024 held in Naxos, Greece, we describe the importance of these neuromodulatory systems in the pathophysiology of select neuropsychiatric disorders, discuss their potential as targets for therapeutic intervention, exploring how they may offer more effective, mechanism-based treatments. We also highlight recent clinical trials, underscoring the progress in advancing towards clinical application, as well as sex-specific neurobiological differences, a historically overlooked, yet fundamental determinant of the pathophysiology of neuropsychiatric disorders. We propose that expanding our focus beyond traditional monoamines offers a promising avenue for the development of new, disease-modifying treatments that can more effectively address the underlying causes of neuropsychiatric disorders. By targeting these pathways, we believe it may be possible to develop therapies that restore balance to dysregulated brain circuits and improve long-term outcomes for patients.

Abstract:
Adult neurogenesis is dysregulated in neurological disorders, including depression. Adult neural stem cells (NSCs) are close to the vasculature and the cerebrospinal fluid, placing them in an ideal position to receive extrinsic signals and transmit these cues to the neurogenic niche. Herein, we aimed to explore how different systemic cues influence the regenerative properties of NSC secretome on recipient differentiating cells and microglia, key neurogenic components. To mimic signals that NSCs may sense in pathological conditions, we used the secretome of oxidative damaged cells (acute oxidative damage), and the serum from depressed mice (depression-associated chronic signals). Alternatively, NSCs were conditioned with different mitochondrial metabolic regulators to mimic a pro-metabolic NSC environment. Results showed that both injury and metabolic stimuli triggered the increase of NSC proliferation and mitochondrial fragmentation, along with the delivery of a neuroprotective secretome toward injured recipient cells. However, premature differentiation was only observed in NSCs sensing depression-associated chronic signals. The secretome from metabolic-stimulated NSCs favored neurogenesis of target cells, being enriched in regenerative metabolites. Depression-associated signals promoted a NSC secretome with reduced regenerative metabolites and microRNAs that repressed microglial phagocytosis and differentiation in target NSCs. At last, the reduction of oxidative phosphorylation-related proteins in the neurogenic niche of depressed mice was rescued by physical exercise. Our data indicate a central role of external metabolic and injury signals in regulating the neurogenic niche through NSC paracrine activity, unveiling distinct NSC regenerative responses upon transient acute and chronic injuries, and new cues for physical exercise-induced alleviation of depression.

Abstract:
Rett Syndrome (RTT, #312750 - OMIM) is a rare, progressive neurodevelopmental X-linked disorder, caused mostly by mutations in the gene for the methyl CpG binding protein 2 (MECP2). MECP2 is a transcriptional and epigenetic regulator that has been proposed to modulate neuronal development and adult neurogenesis, processes disrupted in both RTT patients and mouse models. Cannabidivarin (CBDV), a non-psychotropic cannabinoid, has recently been shown to promote adult neurogenesis through a mechanism mediated by transient receptor potential cation channel subfamily V member 1 (TRPV1). This study aimed to investigate the effects of chronic CBDV administration in a female RTT mouse model. Pre-symptomatic Mecp2(tm1.1Bird/J) female mice underwent a chronic CBDV treatment (3 mg/kg/day), followed by behavioral tests to assess potential therapeutic effects. While CBDV did not prevent deficits in locomotor activity, it mitigated motor coordination impairments in RTT mice. Furthermore, the novel object recognition test suggested that CBDV treatment contributed to the preservation of cognitive function in these animals. Moreover, CBDV administration induced genotype-dependent differences in neural stem cell proliferation, indicating a potential vulnerability in adult hippocampal neurogenesis in Mecp2-deficient contexts. Taken together, these findings provide new insights into the role of CBDV in RTT and support for future research, highlighting its potential as a repurposed therapeutic agent.

Abstract:
Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (G(s)) could rapidly promote the activity of the organelle and possibly compensate for bioenergetic dysfunction. Here, we show that a mitochondria-targeted recombinant designer receptor exclusively activated by designer drugs (mitoDREADD-G(s)) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-G(s) abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer's disease and frontotemporal dementia. Thus, mitoDREADD-G(s) enables the establishment of causal relationships between mitochondria and biological or disease-related processes and represents an innovative potential therapeutic approach for disorders associated with mitochondrial impairment.

Abstract:
Neural stem/progenitor cells (NSPCs) operate in specialized niches of the adult mammalian brain, where their proliferative and differentiative potential is modulated by a myriad of factors. Emerging evidence sheds light on the interaction between cannabinoids and neurotrophic factors underlying a major regulatory force of NSPC dynamics. Previous data show that cannabinoid type 2 receptors (CB2Rs) tightly regulate the actions of brain-derived neurotrophic factor (BDNF), a neurotrophic factor highly upregulated during physical exercise. However, further research into the effects of exercise-associated neurotrophic factors in the regulation of NSPCs is still necessary. Therefore, we aimed at exploring the effects of exercise-associated factors in postnatal hippocampal neurogenesis and how CB2Rs regulate this process. By using dentate gyrus-derived neurospheres and treating them with a combination of exercise-associated factors, as an in vitro proxy for exercise, we found that these factors significantly promoted cell proliferation, an action partially reduced when CB2Rs were blocked. Moreover, CB2Rs were shown to be required for the actions of this exercise-mimicking cocktail in early neuronal commitment and differentiation. However, late neuronal differentiation promoted by exercise-associated factors remained unaltered in the presence of CB2R ligands. Together, these data suggest that CB2R actions are preponderant in early stages of hippocampal neurogenesis promoted by exercise. Astroglial late differentiation was also accelerated by a combination of exercise-associated factors, an effect prevented by CB2R blockage. This work provides a deeper understanding of the mechanisms underlying the actions of cannabinoids and exercise on NSPC regulation, highlighting the role of CB2R in modulating exercise-induced hippocampal neurogenesis.

Abstract:
Neuron-glia interactions are fundamental to the development and function of the nervous system. During development, glia, including astrocytes, microglia, and oligodendrocytes, influence neuronal differentiation and migration, synapse formation and refinement, and myelination. In the mature brain, glia are crucial for maintaining neural homeostasis, modulating synaptic activity, and supporting metabolic functions. Neurons, inherently vulnerable to various stressors, rely on glia for protection and repair. However, glia, in their reactive state, can also promote neuronal damage, which contributes to neurodegenerative and neuropsychiatric diseases. Understanding the dual role of glia-as both protectors and potential aggressors-sheds light on their complex contributions to disease etiology and pathology. By appropriately modulating glial activity, it may be possible to mitigate neurodegeneration and restore neuronal function. In this review, which originated from the International Society for Neurochemistry (ISN) Advanced School in 2019 held in Montreal, Canada, we first describe the critical importance of glia in the development and maintenance of a healthy nervous system as well as their contributions to neuronal damage and neurological disorders. We then discuss potential strategies to modulate glial activity during disease to protect and promote a properly functioning nervous system. We propose that targeting glial cells presents a promising therapeutic avenue for rebuilding the nervous system.

Abstract:
In the original article [...].

Abstract:
Chronic stress is a major risk factor for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects on cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophic factor levels, we hypothesised that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, overall reduction in neuroinflammation, and increased hippocampal levels of BDNF. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasises the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalise on lifestyle interventions complemented with endocannabinoid pharmacomodulation.

Abstract:
Postnatal neurogenesis has been shown to rely on the endocannabinoid system. Here we aimed at unravelling the role of Cannabidivarin (CBDV), a non-psychoactive cannabinoid, with high affinity for the non-classical cannabinoid receptor TRPV1, on subventricular zone (SVZ) postnatal neurogenesis. Using the neurosphere assay, SVZ-derived neural stem/progenitor cells (NSPCs) were incubated with CBDV and/or 5'-Iodoresinferotoxin (TRPV1 antagonist), and their role on cell viability, proliferation, and differentiation were dissected. CBDV was able to promote, through a TRPV1-dependent mechanism, cell survival, cell proliferation and neuronal differentiation. Furthermore, pulse-chase experiments revealed that CBDV-induced neuronal differentiation was a result of cell cycle exit of NSPCs. Regarding oligodendrocyte differentiation, CBDV inhibited oligodendrocyte differentiation and maturation. Since our data suggested that the CBDV-induced modulation of NSPCs acted via TRPV1, a sodium-calcium channel, and that intracellular calcium levels are known regulators of NSPCs fate and neuronal maturation, single cell calcium imaging was performed to evaluate the functional response of SVZ-derived cells. We observed that CBDV-responsive cells displayed a two-phase calcium influx profile, being the initial phase dependent on TRPV1 activation. Taken together, this work unveiled a novel and untapped neurogenic potential of CBDV via TRPV1 modulation. These findings pave the way to future neural stem cell biological studies and repair strategies by repurposing this non-psychoactive cannabinoid as a valuable therapeutic target.

Abstract:
Repeated exposure to psychostimulants, such as amphetamine, causes a long-lasting enhancement in the behavioral responses to the drug, called behavioral sensitization.(1) This phenomenon involves several neuronal systems and brain areas, among which the dorsal striatum plays a key role.(2) The endocannabinoid system (ECS) has been proposed to participate in this effect, but the neuronal basis of this interaction has not been investigated.(3) In the CNS, the ECS exerts its functions mainly acting through the cannabinoid type-1 (CB(1)) receptor, which is highly expressed at terminals of striatal medium spiny neurons (MSNs) belonging to both the direct and indirect pathways.(4) In this study, we show that, although striatal CB(1) receptors are not involved in the acute response to amphetamine, the behavioral sensitization and related synaptic changes require the activation of CB(1) receptors specifically located at striatopallidal MSNs (indirect pathway). These results highlight a new mechanism of psychostimulant sensitization, a phenomenon that plays a key role in the health-threatening effects of these drugs.