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In Parkinson’s disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD. It is unclear if neuromelanin plays a role in Parkinson’s disease pathogenesis since common laboratory animals lack this pigment. Authors show here that overexpression of human tyrosinase in the substantia nigra of rats resulted in an age-dependent production of human-like neuromelanin within nigral dopaminergic neurons and is associated with a Parkinson’s disease phenotype when allowed to accumulate above a specific threshold.

Psychiatric disorders represent a large economic burden in modern societies. However, pharmacological treatments are still far from optimal. Drugs used in the treatment of major depressive disorder (MDD) and anxiety disorders (selective serotonin [5-HT] reuptake inhibitors [SSRIs] and serotonin-noradrenaline reuptake inhibitors [SNRIs]) are pharmacological refinements of first-generation tricyclic drugs, discovered by serendipity, and show low efficacy and slowness of onset. Moreover, antipsychotic drugs are partly effective in positive symptoms of schizophrenia, yet they poorly treat negative symptoms and cognitive deficits. The present article reviews the neurobiological basis of 5-HT 1A receptor (5-HT 1A -R) function and the role of pre- and postsynaptic 5-HT 1A -Rs in the treatment of MDD, anxiety and psychotic disorders. The activation of postsynaptic 5-HT 1A -Rs in corticolimbic areas appears beneficial for the therapeutic action of antidepressant drugs. However, presynaptic 5-HT 1A -Rs play a detrimental role in MDD, since individuals with high density or function of presynaptic 5-HT 1A -Rs are more susceptible to mood disorders and suicide, and respond poorly to antidepressant drugs. Moreover, the indirect activation of presynaptic 5-HT 1A -Rs by SSRIs/SNRIs reduces 5-HT neuron activity and terminal 5-HT release, thus opposing the elevation of extracellular 5-HT produced by blockade of the serotonin transporter (SERT) in the forebrain. Chronic antidepressant treatment desensitizes presynaptic 5-HT 1A -Rs, thus reducing the effectiveness of the 5-HT 1A autoreceptor-mediated negative feedback. The prevention of this process by the non-selective partial agonist pindolol accelerates clinical antidepressant effects. Two new antidepressant drugs, vilazodone (marketed in the USA) and vortioxetine (in development) incorporate partial 5-HT 1A -R agonist properties with SERT blockade. Several studies with transgenic mice have also established the respective role of pre- and postsynaptic 5-HT 1A -Rs in MDD and anxiety. In agreement with pharmacological studies, presynaptic and postsynaptic 5-HT 1A -R activation appears necessary for anxiolytic and antidepressant effects, respectively, yet, neurodevelopmental roles for 5-HT 1A -Rs are also involved. Likewise, the use of small interference RNA has enabled the showing of robust antidepressant-like effects in mice after selective knock-down of 5-HT 1A autoreceptors. Postsynaptic 5-HT 1A -Rs in the prefrontal cortex (PFC) also appear important for the superior clinical effects of clozapine and other second-generation (atypical) antipsychotic drugs in the treatment of schizophrenia and related psychotic disorders. Despite showing a moderate in vitro affinity for 5-HT 1A -Rs in binding assays, clozapine displays functional agonist properties at this receptor type in vivo. The stimulation of 5-HT 1A -Rs in the PFC leads to the distal activation of the mesocortical pathway and to an increased dopamine release in PFC, an effect likely involved in the clinical actions of clozapine in negative symptoms and cognitive deficits in schizophrenia. The anxiolytic/antidepressant properties of 5-HT 1A -R agonists in preclinical tests raised expectations enormously. However, these agents have achieved little clinical success, possibly due to their partial agonist character at postsynaptic 5-HT 1A -Rs, together with full agonist properties at presynaptic 5-HT 1A autoreceptors, as well as their gastrointestinal side effects. The partial 5-HT 1A -R agonists buspirone, gepirone, and tandospirone are marketed as anxiolytic drugs, and buspirone is also used as an augmentation strategy in MDD. The development of new 5-HT 1A -R agonists with selectivity for postsynaptic 5-HT 1A -Rs may open new perspectives in the field.

The superior efficacy of atypical vs. classical antipsychotic drugs to treat negative symptoms and cognitive deficits in schizophrenia appears related to their ability to enhance mesocortical dopamine (DA) function. Given that noradrenergic (NE) transmission contributes to cortical DA output, we assessed the ability of NE-targeting drugs to modulate DA release in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), with the aim of selectively increasing mesocortical DA. Extracellular DA was measured using brain microdialysis in rat mPFC and NAc after local/systemic drug administration, electrical stimulation and selective brain lesions. Local GBR12909 [a selective DA transporter (DAT) inhibitor] administration increased DA output more in NAc than in mPFC whereas reboxetine [a selective NE transporter (NET) inhibitor] had an opposite regional profile. DA levels increased comparably in both regions of control rats after local nomifensine (DAT+NET inhibitor) infusion, but this effect was much lower in PFC of NE-lesioned rats (DSP-4) and in NAc of 6-OHDA-lesioned rats. Electrical stimulation of the locus coeruleus preferentially enhanced DA output in mPFC. Consistently, the administration of reboxetine+RX821002 (an α2-adrenoceptor antagonist) dramatically enhanced DA output in mPFC (but not NAc). This effect also occurred when reboxetine+RX821002 were co-administered with haloperidol or clozapine. The preferential contribution of the NE system to PFC DA allows selective enhancement of DA transmission by simultaneously blocking NET and α2-adrenoceptors, thus preventing the autoreceptor-mediated negative feedback on NE activity. Our results highlight the importance of NET and α2-adrenoceptors as targets for treating negative/cognitive symptoms in schizophrenia and related psychiatric disorders.

Rationale Identifying the etiological factors in anxiety and depression is critical to develop more efficacious therapies. The inhibitory serotonin 1A receptors (5-HT 1A R) located on 5-HT neurons (autoreceptors) limit antidepressant responses and their expression may be increased in treatment-resistant depressed patients. Objectives Recently, we reported that intranasal administration of modified small interference RNA (siRNA) molecules targeting 5-HT 1A R in serotonergic neurons evoked antidepressant-like effects. Here we extended this finding using marketed siRNAs against 5-HT 1A R (1A-siRNA) to reduce directly the 5-HT 1A autoreceptor expression and evaluate its biological consequences under basal conditions and in response to stressful situations. Methods Adult mice were locally infused with vehicle, nonsense siRNA, and 1A-siRNA into dorsal raphe nucleus (DR). 5-HT 1A R knockout mice (1A-KO) were also used. Histological approaches, in vivo microdialysis, and stress-related behaviors were performed to assess the effects of 5-HT 1A autoreceptor knockdown. Results Intra-DR 1A-siRNA infusion selectively reduced 5-HT 1A R mRNA and binding levels and canceled 8-OH-DPAT-induced hypothermia. Basal extracellular 5-HT in medial prefrontal cortex (mPFC) did not differ among treatments. However, 1A-siRNA-treated mice displayed less immobility in the tail suspension and forced swim tests, as did 1A-KO mice. This was accompanied by a greater increase in prefrontal 5-HT release during tail suspension test. Moreover, intra-DR 1A-siRNA infusion augmented the increase of extracellular 5-HT in mPFC evoked by fluoxetine, up to the level in 1A-KO mice. Conclusion Together with our previous report, the present results indicate that acute suppression of 5-HT 1A autoreceptor expression evokes robust antidepressant-like effects, likely mediated by an increased capacity of serotonergic neurons to release 5-HT in stressful conditions.

Anxiety and depression affect 35–50% of patients with Parkinson’s disease (PD), often precede the onset of motor symptoms, and have a negative impact on their quality of life. Dysfunction of the serotonergic (5-HT) system, which regulates mood and emotional pathways, occurs during the premotor phase of PD and contributes to a variety of non-motor symptoms. Furthermore, α-synuclein (α-Syn) aggregates were identified in raphe nuclei in the early stages of the disease. However, there are very few animal models of PD-related neuropsychiatric disorders. Here, we develop a new mouse model of α-synucleinopathy in the 5-HT system that mimics prominent histopathological and neuropsychiatric features of human PD. We showed that adeno-associated virus (AAV5)-induced overexpression of wild-type human α-Syn (h-α-Syn) in raphe 5-HT neurons triggers progressive accumulation, phosphorylation, and aggregation of h-α-Syn protein in the 5-HT system. Specifically, AAV5-injected mice displayed axonal impairment in the output brain regions of raphe neurons, and deficits in brain-derived neurotrophic factor (BDNF) expression and 5-HT neurotransmission, resulting in a depressive-like phenotype. Intracerebroventricular treatment with an indatraline-conjugated antisense oligonucleotide (IND-ASO) for four weeks induced an effective and safe reduction of h-α-Syn synthesis in 5-HT neurons and its accumulation in the forebrain, alleviating early deficits of 5-HT function and improving the behavioural phenotype. Altogether, our findings show that α-synucleinopathy in 5-HT neurons negatively affects brain circuits that control mood and emotions, resembling the expression of neuropsychiatric symptoms occurring at the onset of PD. Early preservation of 5-HT function by reducing α-Syn synthesis/accumulation may alleviate PD-related depressive symptoms.

One key limitation in developing effective treatments for neurodegenerative diseases is the lack of models accurately mimicking the complex physiopathology of the human disease. Humans accumulate with age the pigment neuromelanin inside neurons that synthesize catecholamines. Neurons reaching the highest neuromelanin levels preferentially degenerate in Parkinson’s, Alzheimer’s and apparently healthy aging individuals. However, this brain pigment is not taken into consideration in current animal models because common laboratory species, such as rodents, do not produce neuromelanin. Here we generate a tissue-specific transgenic mouse, termed tgNM, that mimics the human age-dependent brain-wide distribution of neuromelanin within catecholaminergic regions, based on the constitutive catecholamine-specific expression of human melanin-producing enzyme tyrosinase. We show that, in parallel to progressive human-like neuromelanin pigmentation, these animals display age-related neuronal dysfunction and degeneration affecting numerous brain circuits and body tissues, linked to motor and non-motor deficits, reminiscent of early neurodegenerative stages. This model could help explore new research avenues in brain aging and neurodegeneration. Unlike humans, rodents do not accumulate the brain pigment neuromelanin in catecholamine neurons with age. The transgenic mouse model here presented accumulates neuromelanin and mimics the early physiopathology of Parkinson’s disease.

Fast and sustained antidepressant effects of ketamine identified the mammalian target of rapamycin (mTOR) signaling pathway as the main modulator of its antidepressive effects. Thus, mTOR signaling has become integral for the preclinical evaluation of novel compounds to treat depression. However, causality between mTOR and depression has yet to be determined. To address this, we knocked down mTOR expression in mice using an acute intracerebral infusion of small interfering RNAs (siRNA) in the infralimbic (IL) or prelimbic (PrL) cortices of the medial prefrontal cortex (mPFC), and evaluated depressive- and anxious-like behaviors. mTOR knockdown in IL, but not PrL, cortex produced a robust depressive-like phenotype in mice, as assessed in the forced swimming test (FST) and the tail suspension test (TST). This phenotype was associated with significant reductions of mTOR mRNA and protein levels 48 h post-infusion. In parallel, decreased brain-derived neurotrophic factor (BDNF) expression was found bilaterally in both IL and PrL cortices along with a dysregulation of serotonin (5-HT) and glutamate (Glu) release in the dorsal raphe nucleus (DRN). Overall, our results demonstrate causality between mTOR expression in the IL cortex and depressive-like behaviors, but not in anxiety.

Background Parkinson’s disease (PD) is a multisystem disorder frequently comorbid with non-motor symptoms like depressive disorder (DD) and gastrointestinal (GI) dysfunction. Chronic neuroinflammation and disruption of the gut-brain axis are implicated as shared pathological drivers, but the precise molecular mechanisms connecting these conditions remain elusive. We hypothesized that a common microRNA (miRNA)-mediated inflammatory profile underlies this clinical triad, representing a point of pathological convergence. Methods We analyzed the expression of a panel of inflammatory bowel disease (IBD)-associated miRNAs, key inflammatory markers, and glial response in postmortem brain tissue (dorsolateral prefrontal cortex and caudate nucleus) from patients with PD, DD, and matched healthy controls. To investigate causality and gut-brain axis involvement, two mouse models were used: (i) PD-associated α-synucleinopathy was induced in dorsal raphe serotonin (5-HT) neurons; and (ii) DD-like based on corticosterone (CORT)-induced stress. Mice were assessed for depressive-like behaviors and GI dysmotility, and their brain (medial prefrontal cortex and caudate-putamen) and ileum tissues were analyzed for the same molecular markers. Results We identified a conserved miRNA pattern in the brains of both PD and DD patients, characterized by the significant downregulation of miR-199a-5p and miR-219a-5p and the upregulation of miR-200a-3p. This dysregulation was strongly associated with a pro-inflammatory state, as evidenced by increased expression of TNFα, IFN-γ, and NFκB1, as well as changes in the glial response. Mice with α-synucleinopathy in the 5-HT system exhibited a depression-like phenotype and reduced intestinal motility, accompanied by increased Iba1 and GFAP signal. Comparable effects were observed in mice subjected to CORT-induced stress. Notably, the same pattern of miRNAs and inflammatory cytokines observed in the human brain was replicated in the brain and ileum of DD-PD-like mice, providing direct evidence of a parallel pathological process spanning the gut-brain axis. Conclusion This study identifies a specific inflammation-miRNA pathway as a common molecular mechanism connecting the pathophysiology of PD, DD, and gut dysfunction. This pattern represents a critical point of convergence that drives a shared, bidirectional inflammatory cascade along the gut-brain axis. Targeting this miRNA triad could provide a new therapeutic approach for addressing the motor, psychiatric, and GI symptoms of these interconnected disorders simultaneously.

In patients affected by Parkinson’s disease (PD), up to 50% of them experience cognitive changes, and psychiatric disturbances, such as anxiety and depression, often precede the onset of motor symptoms and have a negative impact on their quality of life. Pathologically, PD is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein (α-Syn). Much of PD research has focused on the role of α-Syn aggregates in the degeneration of SNc DA neurons due to the impact of striatal DA deficits on classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the midbrain raphe nuclei, which may contribute to non-motor symptoms. Indeed, dysfunction of the serotonergic (5-HT) system, which regulates mood and emotional pathways, occurs during the premotor phase of PD. However, little is known about the functional consequences of α-Syn inclusions in this neuronal population other than DA neurons. Here, we provide an overview of the current knowledge of α-Syn and its role in regulating the 5-HT function in health and disease. Understanding the relative contributions to α-Syn-linked alterations in the 5-HT system may provide a basis for identifying PD patients at risk for developing depression and could lead to a more targeted therapeutic approach.

Atypical antipsychotic drugs (APDs) increase dopamine (DA) release in prefrontal cortex (PFC), an effect probably mediated by the direct or indirect activation of the 5-HT1A receptor (5-HT1AR). Given the very low in-vitro affinity of most APDs for 5-HT1ARs and the large co-expression of 5-HT1ARs and 5-HT2A receptors (5-HT2ARs) in the PFC, this effect might result from the imbalance of 5-HT1AR and 5-HT2AR activation after blockade of these receptors by APDs, for which they show high affinity. Here we tested this hypothesis by examining the dependence of the APD-induced DA release in medial PFC (mPFC) on each receptor by using in-vivo microdialysis in wild-type (WT) and 5-HT1AR and 5-HT2AR knockout (KO) mice. Local APDs (clozapine, olanzapine, risperidone) administered by reverse dialysis induced a dose-dependent increase in mPFC DA output equally in WT and 5-HT2AR KO mice whereas the DA increase was absent in 5-HT1AR KO mice. To examine the relative contribution of both receptors to the clozapine-induced DA release in rat mPFC, we silenced G-protein-coupled receptors (GPCRs) in vivo with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) while 5-HT1ARs or 5-HT2A/2CRs in the mPFC were selectively protected with the respective antagonists WAY-100635 or ritanserin. The inactivation of GPCRs while preserving ∼70% of 5-HT2A/2CRs prevented the clozapine-induced DA rise in mPFC. In contrast, clozapine increased DA in mPFC of EEDQ-treated rats whose 5-HT1ARs were protected (∼50% of control rats). These results indicate that (1) 5-HT1ARs are necessary for the APDs-induced elevation in cortical DA transmission, and (2) this effect does not require 5-HT2AR blockade by APDs.