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Background: Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents the prodromal stage of cit-synucleinopathies. Reliable biomarkers are needed to predict phenoconversion.Objective: The aim was to derive and validate a brain glucose metabolism pattern related to phenoconversion in iRBD (iRBDconvRP) using spatial covariance analysis (Scaled Subprofile Model and Principal Component Analysis [SSM-PCA]).Methods: Seventy-six consecutive iRBD patients (70 +/- 6 years, 15 women) were enrolled in two centers and prospectively evaluated to assess phenoconversion (30 converters, 73 +/- 6 years, 14 Parkinson's disease and 16 dementia with Lewy bodies, follow-up time: 21 +/- 14 months; 46 nonconverters, 69 +/- 6 years, follow-up time: 33 +/- 19 months). All patients underwent [F-18]FDG-PET (F-18-fluorodeoxyglucose positron emitting tomography) to investigate brain glucose metabolism at baseline. SSM-PCA was applied to obtain the iRBDconvRP; nonconverter patients were considered as the reference group. Survival analysis and Cox regression were applied to explore prediction power.Results: First, we derived and validated two distinct center-specific iRBDconvRP that were comparable and significantly able to predict phenoconversion. Then, SSM-PCA was applied to the whole set, identifying the iRBDconvRP. The iRBDconvRP included positive voxel weights in cerebellum; brainstem; anterior cingulate cortex; lentiform nucleus; and middle, mesial temporal, and postcentral areas. Negative voxel weights were found in posterior cingulate, precuneus, middle frontal gyrus, and parietal areas. Receiver operating characteristic analysis showed an area under the curve of 0.85 (sensitivity: 87%, specificity: 72%), discriminating converters from nonconverters. The iRBDconvRP significantly predicted phenoconversion (hazard ratio: 7.42, 95% confidence interval: 2.6-21.4).Conclusions: We derived and validated an iRBDconvRP to efficiently discriminate converter from nonconverter iRBD patients. [F-18]FDG-PET pattern analysis has potential as a phenoconversion biomarker in iRBD patients. (C) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract: The role of the immune system in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) has become clear in recent decades, as evidenced by the presence of activated microglia and astrocytes and numerous soluble mediators in the brain and peripheral tissues of affected patients. Among inflammatory mediators, chemokines play a central role in neuroinflammation due to their dual function as chemoattractants for immune cells and molecular messengers in crosstalk among CNS-resident cells. The chemokine Bv8/Prokineticin 2 (PK2) has recently emerged as an important player in many age-related and chronic diseases that are either neurodegenerative or systemic. In this perspective paper, we briefly discuss the role that PK2 and its cognate receptors play in AD and PD animal models and in patients. Given the apparent changes in PK2 blood levels in both AD and PD patients, the potential clinical value of PK2 either as a disease biomarker or as a therapeutic target for these disorders is discussed.

Introduction: Parkinson’s disease (PD) is a multisystem disease, involving several brain structures. fMRI studies reported abnormal functional connectivity (FC) in PD. EEG is an accessible method to evaluate cortical activity, which may be used to estimate FC. For this aim, we analyzed differences in FC between patients at early stages of PD and healthy controls (HC) using high-density EEG (HD-EEG). Methods: We enrolled 20 early-stage PD patients and 19 age-matched HC. Data were recorded with a 64-channels HD-EEG system. A source-reconstruction method was used to identify brain-region activity. FC was calculated using a weighted phase-lag index in θ-α-β bands. Network-based statistic was used to compare FC between PD and HC. Results: No statistical-significant differences were observed in spectral analysis between groups. PD patients showed a hypoconnected network in α-band primarily composed by frontal lobe, associated with a hyperconnected network in β band, including frontal, sensorimotor, limbic and temporal areas. Moreover, correlation between β FC in sensorimotor areas and PD motor impairment was found (r = 0.80, p = 0.003). Conclusion: HD-EEG revealed FC alterations since early stages of PD, as a tool complementary to fMRI, and it could be a useful early or even preclinical diagnostic marker of disease.

Persistent olfactory dysfunction (OD) is one of the most complaining and worrying complications of long COVID-19 because of the potential long-term neurological consequences. While causes of OD in the acute phases of the SARS-CoV-2 infection have been figured out, reasons for persistent OD are still unclear. Here we investigated the activity of two inflammatory pathways tightly linked with olfaction pathophysiology, namely Substance P (SP) and Prokineticin-2 (PK2), directly within the olfactory neurons (ONs) of patients to understand mechanisms of persistent post-COVID-19 OD. ONs were collected by non-invasive brushing from ten patients with persistent post-COVID-19 OD and ten healthy controls. Gene expression levels of SP, Neurokinin receptor 1, Interleukin-1β (IL-1β), PK2, PK2 receptors type 1 and 2, and Prokineticin-2-long peptide were measured in ONs by Real Time-PCR in both the groups, and correlated with residual olfaction. Immunofluorescence staining was also performed to quantify SP and PK2 proteins. OD patients, compared to controls, exhibited increased levels of both SP and PK2 in ONs, the latter proportional to residual olfaction. This work provided unprecedented, preliminary evidence that both SP and PK2 pathways may have a role in persistent post-COVID-19 OD. Namely, if the sustained activation of SP, lasting months after infection's resolution, might foster chronic inflammation and contribute to hyposmia, the PK2 expression could instead support the smell recovery.

In a previous study, we observed: (i) significant hearing function impairment, assessed with pure tone audiometry and distortion product otoacoustic emissions, in patients with Parkinson’s disease, compared with a matched control group, and (ii) lateralization of the hearing dysfunction, worse on the side affected by more pronounced Parkinson’s disease motor symptoms. This study investigates the association between the basal ganglia dopamine transporter availability and the hearing function in Parkinson’s disease patients, focusing also on the lateralization of both dysfunctions, with respect to that of the motor symptoms, and introducing a further distinction between patients with left-sided and right-sided predominant motor symptoms. Patients with right-handed Parkinson’s disease with a recent estimation of 123I-FP-CIT striatal uptake were audiologically tested with pure tone audiometry and distortion product otoacoustic emissions. Thirty-nine patients were included in the study. A statistically significant association was found, in the left-side predominant group only, between the distortion product otoacoustic emission levels and the contralateral dopamine transporter availability, and between the hearing threshold and the dopamine transporter availability difference between the ipsi- and the contralateral sides. The hearing impairment lateralization correlated to the motor symptom asymmetry was found significant only in the left-side predominant patients. The association between hearing function and basal ganglia dopamine transporter availability supports the hypothesis that the peripheral hearing function decline associated with dopamine depletion is involved in Parkinson’s disease development, with a significant difference between patients with left- and right-sided predominant motor symptoms. These findings also suggest that peripheral hearing function evaluation and its lateralization could be key elements for subtyping the disease.

The objective of this study was to outline the dynamics of prokineticin-2 pathway in relation to clinical-pathological features of Parkinson's disease by examining olfactory neurons of patients.Thirty-eight patients (26 de novo, newly diagnosed) and 31 sex/age-matched healthy controls underwent noninvasive mucosa brushing for olfactory neurons collection, and standard clinical assessment. Gene expression levels of prokineticin-2, prokineticin-2 receptors type 1 and 2, and prokineticin-2-long peptide were measured in olfactory neurons by real-time polymerase chain reaction (PCR); moreover, the prokineticin-2 protein and α-synuclein species (total and oligomeric) were quantified by immunofluorescence staining.Prokineticin-2 expression was significantly increased in Parkinson's disease. De novo patients had higher prokineticin-2 levels, directly correlated with Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III motor score. In addition, oligomeric α-synuclein was higher in Parkinson's disease and directly correlated with prokineticin-2 protein levels. Total α-synuclein did not differ between patients and controls.Prokineticin-2 is a chemokine showing neuroprotective effects in experimental models of Parkinson's disease, but translational proof of its role in patients is still lacking. Here, we used olfactory neurons as the ideal tissue to analyze molecular stages of neurodegeneration in vivo, providing unprecedented evidence that the prokineticin-2 pathway is activated in patients with Parkinson's disease. Specifically, prokineticin-2 expression in olfactory neurons was higher at early disease stages, proportional to motor severity, and associated with oligomeric α-synuclein accumulation. These data, consistently with preclinical findings, support prokineticin-2 as a candidate target in Parkinson's disease, and validate reliability of olfactory neurons to reflect pathological changes of the disease. ANN NEUROL 2022.

Child maltreatment disrupts trajectories of brain development, but the underlying pathways are unclear. Stressful stimuli in early life interfere with maturation of local inhibitory circuitry and deposition of perineuronal nets (PNNs), specialized extracellular matrix structures involved in the closure of critical periods of development. Alterations in cortical PNN and parvalbumin (PV) following early-life stress (ELS) have been detected in human and animal studies. Aberrations in the anterior cingulate cortex (ACC) are the most consistent neuroimaging findings in maltreated people, but the molecular mechanisms linking ELS with ACC dysfunctions are unknown. Here, we employed a mouse model of early social threat to test whether ELS experienced in a sensitive period for ACC maturation could induce long-term aberrations of PNN and PV development in the ACC, with consequences on plasticity and ACC-dependent behavior. We found that ELS increased PNN but not PV expression in the ACC of young adult mice. This was associated with reduced frequency of inhibitory postsynaptic currents and long-term potentiation impairments and expression of intense object phobia. Our findings provide information on the long-term effects of ELS on ACC functionality and PNN formation and present evidence for a novel neurobiological pathway underlying the impact of early adversity on the brain.

In Parkinson's disease (PD), cortical-subcortical interplay plays a relevant role in affecting clinical performance. Functional MRI sequences described changes in functional connectivity at different stages of disease. Scarce are, instead, the investigations examining brain connectivity in patients with PD at early stages of disease. For this aim, here we analyzed the differences in functional connectivity between

In oncology, comprehensive omics and functional enrichment studies have led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor’s clinical phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging the real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields, including psychiatry and neurology. In order to illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the β-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer’s disease, schizoaffective disorder, and autism spectrum disorders. To facilitate a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom-agnostic, categorization models in clinical neurology and psychiatry for precision medicine solutions, we engage in a speculative intellectual exercise gravitating around BACE-related science, which is used as a paradigmatic case here. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by highthroughput techniques embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in neurology and psychiatry.

Recently, monoclonal antibodies (mAbs) directed against calcitonin gene-related peptide (CGRP) (Eptinezumab, Fremanezumab, and Galcanezumab) or its receptor (Erenumab) have been approved for clinical use as prophylactic drugs for high-frequency episodic and chronic migraine. While their therapeutic effects on headache pain is well documented, there is scarce information on the usefulness of these medications in preventing migraine aura, which is believed to be associated with cortical spreading depression (CSD). Because of their large size, mAbs cannot easily cross the blood–brain barrier in high quantities, rendering the peripheral trigeminovascular system to likely be a major site of their action. In this paper, we report two cases of patients suffering from migraine with and without aura, who reported a complete disappearance of aura or reduced aura duration and intensity while taking Galcanezumab or Erenumab, respectively. Then, we present a brief overview of the literature about the controversial relationship between CSD and CGRP and about the potential “additional central” role of these mAbs in the pathophysiology of migraine aura.

Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early‐onset DYT1 dystonia. Nevertheless, the mechanisms that regulate D2 receptor signaling in health and disease remain poorly understood. Here, we identify a reduced D2 receptor binding, paralleled by an abrupt reduction in receptor protein level, in the striatum of juvenile Dyt1 mice. This occurs through increased lysosomal degradation, controlled by competition between β‐arrestin 2 and D2 receptor binding proteins. Accordingly, we found lower levels of striatal RGS9‐2 and spinophilin. Further, we show that genetic depletion of RGS9‐2 mimics the D2 receptor loss of DYT1 dystonia striatum, whereas RGS9‐2 overexpression rescues both receptor levels and electrophysiological responses in Dyt1 striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in Dyt1 mice and in turn explains why dopaminergic drugs lack efficacy in DYT1 patients despite significant evidence for striatal D2 receptor dysfunction. Our data also open up novel avenues for disease‐modifying therapeutics to this incurable neurological disorder.

Background. In order to raise the level of investor’s protection, the European Commission has recently introduced the Key Investor Information Document (KIID), a standard, plainly worded, consumer-friendly document which should provide individuals with essential information for their investment decisions. KIID layout has been delineated relying on results from focus groups, surveys and telephone interviews, ignoring the reliable and unbiased insights offered by neuroscientific approaches. Aim. The current study aims to elucidate the patterns of eye movements in the early phases of information acquisition during the reading of financial disclosure documents, disentangling the independent role of information color and impulsivity at modulating attention distribution towards the different sources of financial information. Materials and Methods. Oculomotor behavior was monitored in eighty-one healthy adults through the eye tracking technology (SMI REDn Scientific 60Hz). An ecological protocol exploiting official KIIDs was developed to control for several individual variables, through delivering standard visual stimuli based on official financial documents. Participants performed a passive exploration task (with the only specific instruction of visually exploring the document), followed by an active task where they were asked to rate the financial attractiveness of the products, as low, medium or high. The Barratt impulsiveness scale (BIS-11) was administered to each participant, to score such personality trait. Results. Attention distribution over the different information sources, included in the KIIDs, has been quantified and found to be independently modulated by both color and impulsivity, with a greater role of the former over the latter. The addition of either red or blue information to some KIID’s sections increases attention allocation towards the whole document, compared to the usual black and white version. BIS-11 total scores were inversely related to the first and average fixation duration in the neutral, though not in the colored condition. Discussion. Bottom-up, stimulus-related mechanisms of attention allocation influence information acquisition during the reading of financial prospectuses to the point that the increased attention induced by color compensates for individual impulsivity. Such evidence should be considered by regulators when devising the disclosure documents in order to increase investors’ protection.

Significant advances have been made in the understanding of the numerous mechanisms involved in Parkinson's disease (PD) pathogenesis. The identification of PD pathogenic mutations and the use of different animal models have contributed to better elucidate the processes underlying the disease. Here, we report a brief survey of some relevant cellular mechanisms, including autophagic-lysosomal dysfunction, endoplasmic reticulum stress, and mitochondrial impairment, with the main aim to focus on their potential convergent roles in determining early alterations at the synaptic level, mainly consisting in a decrease in dopamine release at nigrostriatal terminals and loss of synaptic plasticity at corticostriatal synapses. In a number of experimental models, this synaptopathy has been shown to be an initial, central event in PD pathogenesis, preceding neuronal damage, thereby representing a valuable tool for testing potential disease-modifying treatments.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease whose pathophysiological deficits, causing impairment in motor function, are largely unknown. Here we propose that hydrogen sulfide (H2 S), as a glial-released inflammatory factor, contributes to ALS-mediated motor neuron death.H2 S concentrations were analyzed in the cerebrospinal fluid of 37 sporadic ALS patients and 14 age- and gender-matched controls, in tissues of a familial ALS (fALS) mouse model, and in spinal cord culture media by means of a specific and innovative high-performance liquid chromatography method. The effects of H2 S on motor neurons cultures was analyzed immunohistochemically and by patch clamp recordings and microfluorometry.We found a significantly high level of H2 S in the spinal fluid of the ALS patients. Consistently, we found increased levels of H2 S in the tissues and in the media from mice spinal cord cultures bearing the fALS mutation SOD1G93A. In addition, NaHS, an H2 S donor, added to spinal culture, obtained from control C57BL/6J mice, is toxic for motor neurons, and induces an intracellular Ca(2+) increase, attenuated by the intracytoplasmatic application of adenosine triphosphate. We further show that H2 S is mainly released by astrocytes and microglia.This study unravels H2 S as an astroglial mediator of motor neuron damage possibly involved in the cellular death characterizing ALS.

Abnormal dopamine (DA) transmission in the striatum plays a pivotal role in attention-deficit/hyperactivity disorder (ADHD). As striatal DA signalling modulates the endocannabinoid system (ECS), the present study was aimed at investigating cannabinoid CB1 receptor (CB1R) function in a model of ADHD obtained by triple point-mutation in the dopamine transporter (DAT) gene in mice, making them insensitive to cocaine [DAT cocaine-insensitive (DAT-CI) mice]. DAT-CI mice had a marked hyperactive phenotype, and neurophysiological recordings revealed that the sensitivity of CB1Rs controlling GABA-mediated synaptic currents [CB1Rs((GABA)) ] in the striatum was completely lost. In contrast, CB1Rs modulating glutamate transmission [CB1Rs((Glu)) ], and GABA(B) receptors were not affected in this model of ADHD. In DAT-CI mice, the blockade of CB1R((GABA)) function was complete even after cocaine or environmental manipulations activating the endogenous DA-dependent reward system, which are known to sensitize these receptors in control animals. Conversely, the hedonic property of sucrose was intact in DAT-CI mice, indicating normal sweet perception in these animals. Our results point to CB1Rs as novel molecular players in ADHD, and suggest that therapeutic strategies aimed at interfering with the ECS might prove effective in this disorder.

Organotypic cultures (OCs) have been widely used to investigate the midbrain dopaminergic system, but only a few studies focused on the functional properties of dopaminergic neurons and their synaptic inputs from dopaminergic and non-dopaminergic neurons also contained in such cultures. In addition, it is not clear whether the culturing process affects the intrinsic neuronal properties and the expression of specific receptors and transporters. We performed patch-clamp recordings from dopaminergic neurons in mesencephalic-striatal co-cultures obtained from transgenic mice expressing green fluorescent protein (GFP) under the tyrosine hydroxylase promoter. Some (10/44) GFP+ neurons displayed a bursting activity that renders the firing of these cells similar to that of the dopaminergic neurons in vivo. The culturing process reduced the hyperpolarization-activated current (I(h) ) and the expression of D₂ receptors. Downregulation of D₂ receptor mRNA and protein was confirmed with reverse transcriptase polymerase chain reaction and Western blotting. Immunocytochemistry revealed that many synaptic terminals, most likely originating from dopaminergic neurons, co-expressed the dopamine (DA) transporter and the vesicular glutamate transporter-2, suggesting a co-release of DA and glutamate. Interestingly, exogenous DA decreased glutamate release in young cultures [days in vitro (DIV)20] by acting on pre-synaptic D₂ receptors, while in older cultures (DIV26) DA increased glutamate release by acting on α-1 adrenoreceptors. The facilitatory effect of DA on glutamatergic transmission to midbrain dopaminergic neurons may be important in conditions when the expression of D₂ receptors is compromised, such as long-term treatment with antipsychotic drugs. Our data show that midbrain OCs at DIV26 may provide a suitable model of such conditions.

Trace amines (TAs) are a class of endogenous compounds strictly related to classic monoamine neurotransmitters with regard to their structure, metabolism, and tissue distribution. Although the presence of TAs in mammalian brain has been recognized for decades, until recently they were considered to be by-products of amino acid metabolism or as "false" neurotransmitters. The discovery in 2001 of a new family of G-protein-coupled receptors (GPCRs), namely trace amines receptors, has re-ignited interest in TAs. In particular, two members of the family, trace amine receptor 1 (TA(1)) and trace amine receptor 2 (TA(2)), were shown to be highly sensitive to these endogenous compounds. Experimental evidence suggests that TAs modulate the activity of catecholaminergic neurons and that TA dysregulation may contribute to neuropsychiatric disorders, including schizophrenia, attention deficit hyperactivity disorder, depression and Parkinson's disease, all of which are characterized by altered monoaminergic networks. Here we review recent data concerning the electrophysiological effects of TAs on the activity of mesencephalic dopaminergic neurons. In the context of recent data obtained with TA(1) receptor knockout mice, we also discuss the mechanisms by which the activation of these receptors modulates the activity of these neurons. Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABA(B) receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA(1) receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. While the first two effects have been well documented in our laboratory, the direct activation of GIRK channels by TA(1) receptors has been reported by others, but has not been seen in our laboratory (Geracitano et al., 2004). Further research is needed to address this point, and to further characterize the mechanism of action of TAs on dopaminergic neurons.

The substantia nigra, located in the ventral mesencephalon, is one of the five nuclei that constitute the basal ganglia circuit, which controls voluntary movements. It is divided into the pars compacta and the pars reticulata, which mainly contain dopaminergic and GABAergic cells respectively. Here we overview the electrophysiological properties of these substantia nigra neurons in the pars compacta and reticulata, together with their synaptic connections, and discuss the functional effects of dopaminergic and GABAergic inputs within the basal ganglia. We also examine the phenomenon that when a deficiency of dopamine (DA) occurs (e.g. in Parkinson's disease), there is an aberrant synaptic plasticity in the basal ganglia. Moreover, we point out that the appearance of an altered pattern of neuronal firing (beta-oscillations) and synchrony among neurons in the subthalamic nucleus, the internal globus pallidus, and the substantia nigra pars reticulata has been related to motor symptoms and possibly, persistent degeneration of DA-containing neurons. Finally, we believe that, based on pathophysiological data, new and significant targets for therapeutic intervention can be identified and tested.

Rotenone is a toxin used to generate animal models of Parkinson's disease; however, the mechanisms of toxicity in substantia nigra pars compacta (SNc) neurons have not been well characterized. We have investigated rotenone (0.05-1 microm) effects on SNc neurons in acute rat midbrain slices, using whole-cell patch-clamp recording combined with microfluorometry. Rotenone evoked a tolbutamide-sensitive outward current (94 +/- 15 pA) associated with increases in intracellular [Ca(2+)] ([Ca(2+)](i)) (73.8 +/- 7.7 nm) and intracellular [Na(+)] (3.1 +/- 0.6 mm) (all with 1 microm). The outward current was not affected by a high ATP level (10 mm) in the patch pipette but was decreased by Trolox. The [Ca(2+)](i) rise was abolished by removing extracellular Ca(2+), and attenuated by Trolox and a transient receptor potential M2 (TRPM2) channel blocker, N-(p-amylcinnamoyl) anthranilic acid. Other effects included mitochondrial depolarization (rhodamine-123) and increased mitochondrial reactive oxygen species (ROS) production (MitoSox), which was also abolished by Trolox. A low concentration of rotenone (5 nm) that, by itself, did not evoke a [Ca(2+)](i) rise resulted in a large (46.6 +/- 25.3 nm) Ca(2+) response when baseline [Ca(2+)](i) was increased by a 'priming' protocol that activated voltage-gated Ca(2+) channels. There was also a positive correlation between 'naturally' occurring variations in baseline [Ca(2+)](i) and the rotenone-induced [Ca(2+)](i) rise. This correlation was not seen in non-dopaminergic neurons of the substantia nigra pars reticulata (SNr). Our results show that mitochondrial ROS production is a key element in the effect of rotenone on ATP-gated K(+) channels and TRPM2-like channels in SNc neurons, and demonstrate, in these neurons (but not in the SNr), a large potentiation of rotenone-induced [Ca(2+)](i) rise by a small increase in baseline [Ca(2+)](i).

Hydrogen peroxide (H2O2) is a reactive oxygen species, responsible for cytotoxic damage through the formation of hydroxyl radicals. Dopamine (DA) neurones of the substantia nigra pars compacta (SNc) are highly sensitive to metabolic stress, and they typically respond to energy deprivation with membrane hyperpolarization, mainly through opening of ATP-dependent K+ channels. Accordingly, H2O2 (3 mm) induced a tolbutamide-sensitive outward current in DA neurones. Conversely, in a hypoxic medium, H2O2 reverted membrane hyperpolarization, which is associated with oxygen deprivation in DA neurones, restored their action potential firing, and reduced the hypoxia-mediated outward current in a concentration-dependent manner, between 0.1 and 3 mm (IC50 0.6 ± 0.1 mm). Notably, H2O2 did not counteract membrane hyperpolarization associated with hypoglycaemia, moreover, when catalase was inhibited with 3-amino-1,2,4-triazole (3-AT; 30 mm), H2O2 did not reduce hypoxia-mediated outward current. The counteracting action of H2O2 on hypoxia-mediated effects was further confirmed by single-unit extracellular recordings of presumed DA neurones in acute midbrain slices preparations, using a planar multi-electrode array device. Whilst a prolonged period of hypoxia (40 min) caused firing suppression, which did not recover after perfusion in normoxic conditions, the presence of H2O2 (3 mm) during this prolonged hypoxic period rescued most of the neurones from irreversible firing inhibition. Accordingly, morphological studies showed that H2O2 counteracts the cytochrome c release provoked by prolonged hypoxic treatment. Taken together, our data suggest that H2O2 prevents the metabolic stress of DA neurones induced by hypoxia by serving as a supplementary source of molecular oxygen, through its degradation by catalase.

Transient receptor potential (TRP) channels form cationic channels activated by diverse factors including mechanical stimuli, changes in osmolarity, pH and temperature, as well as the exogenous irritant, capsaicin. Metabotropic glutamate receptors have also recently been linked to TRP channel activation in neurones of the substantia nigra, hippocampus and cerebellum, suggesting a novel role for such channels in synaptic communication via endogenous neurotransmitters. We tested this for dopamine neurones in rat brain slices by characterizing the current-voltage relationship and pharmacology of EPSCs mediated by group I metabotropic glutamate receptor subtype 1 (mGluR1). Slow inward currents (273 +/- 35 pA peak amplitude, 381 +/- 25 ms latency, holding potential (V(h)) =-73 mV) representing evoked mGluR1 EPSCs were isolated in the presence of antagonists of AMPA, NMDA, GABA(A), GABA(B), muscarinic and glycine receptors. CPCCOEt (100 microM), an mGluR1 antagonist, blocked the residual EPSC in all recordings. mGluR1-activated EPSCs reversed polarity near -10 mV, consistent with the involvement of a cationic channel. Extracellular application of the non-selective TRP channel blockers SKF 96365, flufenamic acid and ruthenium red caused reversible inhibition of mGluR1-activated EPSCs. These characteristics parallel those of mGluR1 activation with an agonist and indicate the involvement of a TRP-like channel in mGluR1-mediated EPSCs.

Novakovic D, Feligioni M, Scaccianoce S, et al. Drug Des Devel Ther. 2013;7:1359–1364.On page 1362, left hand column, last sentence under Functional studies:The effects of gantenerumab on cognitive assessment in the Morris water maze test were inconclusive, as both wild-type and transgenic AD mice injected with vehicle displayed impairment of learning, which might be ascribed to stress conditions caused by weekly intracerebroventricular injections. Importantly, neurological or motor impairments were not detected even after 5 months of treatment.24Should read as:The effects of gantenerumab on cognitive assessment in the Morris water maze test were inconclusive, as both wild-type and transgenic AD mice injected with vehicle displayed impairment of learning, which might be ascribed to stress conditions caused by weekly intravenous injections. Importantly, neurological or motor impairments were not detected even after 5 months of treatment.24Read the original article

Unilateral 6-hydroxydopamine-induced lesions of the substantia nigra have been used as an experimental model for Parkinson's disease. Although the biochemical and the behavioural effects of striatal denervation have been widely characterized, the physiological and pharmacological changes caused by dopamine depletion at the cellular level are still unknown. We studied the electrical activity of single rat striatal neurons recorded intracellularly in vitro from a brain slice preparation. Recordings were obtained at different periods after the denervation (4, 6, 8 months). In dopamine-denervated slices, unlike naive slices, most of the neurons showed spontaneous depolarizing postsynaptic potentials. The percentage of cells showing spontaneous depolarizing postsynaptic potentials was maximal 4 months after the denervation. In most of the dopamine-denervated neurons (60%) spontaneous depolarizing postsynaptic potentials were reversibly blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), an antagonist of non-N-methyl-D-aspartate glutamate receptors. In some neurons, however, the amplitude of spontaneous depolarizing postsynaptic potentials was reduced by bicuculline (30 microM) suggesting that they were mediated by the release of endogenous gamma-aminobutyric acid (GABA). Intrinsic membrane properties (membrane potential, input resistance and firing pattern) and postsynaptic responses to different agonists of excitatory amino acid receptors were not altered in neurons recorded from dopamine-depleted slices. In dopamine-depleted slices, unlike in naive slices, LY 171555 (0.1-10 microM), a D2 dopamine receptor agonist, reduced the frequency and the amplitude of CNQX-sensitive spontaneous depolarizing postsynaptic potentials and reduced the amplitude of glutamate-mediated synaptic potentials evoked by cortical stimulation. LY 171555 did not affect the membrane responses to exogenous glutamate. SKF 38393 (3 microM), a D1 dopamine receptor agonist, decreased postsynaptic excitability of striatal neurons recorded from naive animals. On the contrary, this agonist was ineffective in most of the cells obtained from dopamine-depleted slices. These results suggest that dopamine-denervation augments neuronal excitability in the striatum. Abnormal excitability of striatal neurons is not caused by changes of the intrinsic membrane properties of these cells, but is the result of increased glutamatergic cortical inputs to the striatum. Dopamine-denervation also alters the physiological responses to dopamine receptor stimulation. Nigral lesions induce supersensitivity of D2 dopamine receptors controlling the release of glutamate and reduce the inhibitory influence of D1 receptors at postsynaptic level. These functional changes of the striatal neurons may alter the output signals from the striatum to the other structures of the basal ganglia and then produce most of the physiopathological changes observed in Parkinson's disease.