Publications by authors named "Valentina Chiodi"

18 Publications

  • Page 1 of 1

Insight into the Role of the STriatal-Enriched Protein Tyrosine Phosphatase (STEP) in A Receptor-Mediated Effects in the Central Nervous System.

Front Pharmacol 2021 19;12:647742. Epub 2021 Apr 19.

National Centre for Drug Research and Evaluation, Istituto Superiore di Sanitá, Rome, Italy.

The STriatal-Enriched protein tyrosine phosphatase STEP is a brain-specific tyrosine phosphatase that plays a pivotal role in the mechanisms of learning and memory, and it has been demonstrated to be involved in several neuropsychiatric diseases. Recently, we found a functional interaction between STEP and adenosine A receptor (AR), a subtype of the adenosine receptor family widely expressed in the central nervous system, where it regulates motor behavior and cognition, and plays a role in cell survival and neurodegeneration. Specifically, we demonstrated the involvement of STEP in AR-mediated cocaine effects in the striatum and, more recently, we found that in the rat striatum and hippocampus, as well as in a neuroblastoma cell line, the overexpression of the AR, or its stimulation, results in an increase in STEP activity. In the present article we will discuss the functional implication of this interaction, trying to examine the possible mechanisms involved in this relation between STEP and ARs.
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http://dx.doi.org/10.3389/fphar.2021.647742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090931PMC
April 2021

Sialylated human milk oligosaccharides program cognitive development through a non-genomic transmission mode.

Mol Psychiatry 2021 Mar 4. Epub 2021 Mar 4.

Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.

Breastmilk contains bioactive molecules essential for brain and cognitive development. While sialylated human milk oligosaccharides (HMOs) have been implicated in phenotypic programming, their selective role and underlying mechanisms remained elusive. Here, we investigated the long-term consequences of a selective lactational deprivation of a specific sialylated HMO in mice. We capitalized on a knock-out (KO) mouse model (B6.129-St6gal1/J) lacking the gene responsible for the synthesis of sialyl(alpha2,6)lactose (6'SL), one of the two sources of sialic acid (Neu5Ac) to the lactating offspring. Neu5Ac is involved in the formation of brain structures sustaining cognition. To deprive lactating offspring of 6'SL, we cross-fostered newborn wild-type (WT) pups to KO dams, which provide 6'SL-deficient milk. To test whether lactational 6'SL deprivation affects cognitive capabilities in adulthood, we assessed attention, perseveration, and memory. To detail the associated endophenotypes, we investigated hippocampal electrophysiology, plasma metabolomics, and gut microbiota composition. To investigate the underlying molecular mechanisms, we assessed gene expression (at eye-opening and in adulthood) in two brain regions mediating executive functions and memory (hippocampus and prefrontal cortex, PFC). Compared to control mice, WT offspring deprived of 6'SL during lactation exhibited consistent alterations in all cognitive functions addressed, hippocampal electrophysiology, and in pathways regulating the serotonergic system (identified through gut microbiota and plasma metabolomics). These were associated with a site- (PFC) and time-specific (eye-opening) reduced expression of genes involved in central nervous system development. Our data suggest that 6'SL in maternal milk adjusts cognitive development through a short-term upregulation of genes modulating neuronal patterning in the PFC.
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http://dx.doi.org/10.1038/s41380-021-01054-9DOI Listing
March 2021

The activity of the Striatal-enriched protein tyrosine phosphatase in neuronal cells is modulated by adenosine A receptor.

J Neurochem 2020 02 10;152(3):284-298. Epub 2019 Oct 10.

National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy.

We recently demonstrated that a tonic activation of adenosine A receptors (A Rs) is required for cocaine-induced synaptic depression and increase in the activity of STriatal-Enriched protein tyrosine Phosphatase (STEP). In this study, we elaborated on the relationship between A R and STEP using genetic, pharmacological, and cellular tools. We found that the activities of protein tyrosine phosphatases (PTPs), and in particular of STEP, are significantly increased in the striatum and hippocampus of a transgenic rat strain over-expressing the neuronal A R (NSEA ) with respect to wild-type (WT) rats. Moreover the selective A R agonist 4-[2-[[6-Amino-9-(N-ethyl-β-d-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride up-regulates PTPs and STEP activities in WT but not in NSEA rats, while the selective A R antagonist 4-(-2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a} {1,3,5}triazin-5-yl-amino]ethyl)phenol restores the tyrosine phosphatase activities in NSEA , having no effects in WT rats. In addition, while cocaine induced the activation of PTP and STEP in WT rats, it failed to increase phosphatase activity in NSEA rats. A Rs modulate STEP activity also in the SH-SY5Y neuroblastoma cell line, where a calcium-dependent calcineurin/PP1 pathway was found to play a major role. In summary, the present study identified a novel interaction between A R and STEP that could have important clinical implications, since STEP has emerged as key regulator of signaling pathways involved in neurodegenerative and neuropsychiatric diseases and A Rs are considered a promising target for the development of therapeutic strategies for different diseases of the central nervous system. Read the Editorial Highlight for this article on page 270.
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http://dx.doi.org/10.1111/jnc.14866DOI Listing
February 2020

Adenosine A receptor as potential therapeutic target in neuropsychiatric disorders.

Pharmacol Res 2019 09 2;147:104338. Epub 2019 Jul 2.

National Centre for Drug Research and Evaluation, Istituto Superiore di Sanità, Roma, Italy.

Adenosine A receptor (AR) is a G-protein coupled receptor that regulates several important functions in the central nervous system. Large amount of preclinical data suggests that the AR could represent a target for the development of new therapeutic strategies for different neuropsychiatric conditions. In this review we will recapitulate and discuss the most relevant studies on the role of ARs in neurodegenerative, neurodevelopmental and psychiatric diseases, which led to suggest a therapeutic use of AR agonists in certain diseases (Niemann-Pick disease, autism-spectrum disorders, schizophrenia) and AR antagonists in others (Alzheimer's disease, Parkinson's disease, attention-deficit hyperactivity disorder, fragile X syndrome, depression, anxiety). Moreover, we will try to analyze which are the main obstacles to the conduction of clinical trials with AR ligands for the treatment of neuropsychiatric disease.
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http://dx.doi.org/10.1016/j.phrs.2019.104338DOI Listing
September 2019

Neuronal adenosine A receptor overexpression is neuroprotective towards 3-nitropropionic acid-induced striatal toxicity: a rat model of Huntington's disease.

Purinergic Signal 2018 09 16;14(3):235-243. Epub 2018 May 16.

National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy.

The A adenosine receptor (AR) is widely distributed on different cellular types in the brain, where it exerts a broad spectrum of pathophysiological functions, and for which a role in different neurodegenerative diseases has been hypothesized or demonstrated. To investigate the role of neuronal ARs in neurodegeneration, we evaluated in vitro and in vivo the effect of the neurotoxin 3-nitropropionic acid (3-NP) in a transgenic rat strain overexpressing ARs under the control of the neural-specific enolase promoter (NSEA rats). We recorded extracellular field potentials (FP) in corticostriatal slice and found that the synaptotoxic effect of 3-NP was significantly reduced in NSEA rats compared with wild-type animals (WT). In addition, after exposing corticostriatal slices to 3-NP 10 mM for 2 h, we found that striatal cell viability was significantly higher in NSEA rats compared to control rats. These in vitro results were confirmed by in vivo experiments: daily treatment of female rats with 3-NP 10 mg/kg for 8 days induced a selective bilateral lesion in the striatum, which was significantly reduced in NSEA compared to WT rats. These results demonstrate that the overexpression of the AR selectively at the neuronal level reduced 3-NP-induced neurodegeneration, and suggest an important function of the neuronal AR in the modulation of neurodegeneration.
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http://dx.doi.org/10.1007/s11302-018-9609-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107463PMC
September 2018

Striatal adenosine-cannabinoid receptor interactions in rats over-expressing adenosine A2A receptors.

J Neurochem 2016 Mar 24;136(5):907-17. Epub 2015 Nov 24.

Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.

Adenosine A2A receptors (A2 A Rs) and cannabinoid CB1 receptors (CB1 Rs) are highly expressed in the striatum, where they functionally interact and form A2A /CB1 heteroreceptor complexes. We investigated the effects of CB1 R stimulation in a transgenic rat strain over-expressing A2 A Rs under the control of the neural-specific enolase promoter (NSEA2A rats) and in age-matched wild-type (WT) animals. The effects of the CB1 R agonist WIN 55,212-2 (WIN) were significantly lower in NSEA2A rats than in WT animals, as demonstrated by i) electrophysiological recordings of synaptic transmission in corticostriatal slices; ii) the measurement of glutamate outflow from striatal synaptosomes and iii) in vivo experiments on locomotor activity. Moreover, while the effects of WIN were modulated by both A2 A R agonist (CGS 21680) and antagonists (ZM 241385, KW-6002 and SCH-442416) in WT animals, the A2 A R antagonists failed to influence WIN-mediated effects in NSEA2A rats. The present results demonstrate that in rats with genetic neuronal over-expression of A2 A Rs, the effects mediated by CB1 R activation in the striatum are significantly reduced, suggesting a change in the stoichiometry of A2A and CB1 receptors and providing a strategy to dissect the involvement of A2 A R forming or not forming heteromers in the modulation of striatal functions. These findings add additional evidence for the existence of an interaction between striatal A2 A Rs and CB1 Rs, playing a fundamental role in the regulation of striatal functions. We studied A2A -CB1 receptor interaction in transgenic rats over-expressing adenosine A2A receptors under the control of the neuron-specific enolase promoter (NSEA2A ). In these rats, we demonstrated a reduced effect of the CB1 receptor agonist WIN 55,212-2 in the modulation of corticostriatal synaptic transmission and locomotor activity, while CB1 receptor expression level did not change with respect to WT rats. A reduction in the expression of A2A -CB1 receptor heteromers is postulated.
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http://dx.doi.org/10.1111/jnc.13421DOI Listing
March 2016

Long-lasting beneficial effects of central serotonin receptor 7 stimulation in female mice modeling Rett syndrome.

Front Behav Neurosci 2015 14;9:86. Epub 2015 Apr 14.

Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità Rome, Italy.

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that specific behavioral and brain molecular alterations can be rescued in MeCP2-308 male mice, a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family-crucially involved in the regulation of brain structural plasticity and cognitive processes-can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective 5-HT7R agonist. The present study extends previous findings by demonstrating that the LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues RTT-related phenotypic alterations, motor coordination (Dowel test), spatial reference memory (Barnes maze test) and synaptic plasticity (hippocampal long-term-potentiation) in MeCP2-308 heterozygous female mice, the genetic and hormonal milieu that resembles that of RTT patients. LP-211 also restores the activation of the ribosomal protein (rp) S6, the downstream target of mTOR and S6 kinase, in the hippocampus of RTT female mice. Notably, the beneficial effects on neurobehavioral and molecular parameters of a seven-day long treatment with LP-211 were evident up to 2 months after the last injection, thus suggesting long-lasting effects on RTT-related impairments. Taken together with our previous study, these results provide compelling preclinical evidence of the potential therapeutic value for RTT of a pharmacological approach targeting the brain 5-HT7R.
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http://dx.doi.org/10.3389/fnbeh.2015.00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396444PMC
April 2015

Modulation of Rho GTPases rescues brain mitochondrial dysfunction, cognitive deficits and aberrant synaptic plasticity in female mice modeling Rett syndrome.

Eur Neuropsychopharmacol 2015 Jun 30;25(6):889-901. Epub 2015 Mar 30.

Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Roma, Italy.

Rho GTPases are molecules critically involved in neuronal plasticity and cognition. We have previously reported that modulation of brain Rho GTPases by the bacterial toxin CNF1 rescues the neurobehavioral phenotype in MeCP2-308 male mice, a model of Rett syndrome (RTT). RTT is a rare X-linked neurodevelopmental disorder and a genetic cause of intellectual disability, for which no effective therapy is available. Mitochondrial dysfunction has been proposed to be involved in the mechanism of the disease pathogenesis. Here we demonstrate that modulation of Rho GTPases by CNF1 rescues the reduced mitochondrial ATP production via oxidative phosphorylation in the brain of MeCP2-308 heterozygous female mice, the condition which more closely recapitulates that of RTT patients. In RTT mouse brain, CNF1 also restores the alterations in the activity of the mitochondrial respiratory chain (MRC) complexes and of ATP synthase, the molecular machinery responsible for the majority of cell energy production. Such effects were achieved through the upregulation of the protein content of those MRC complexes subunits, which were defective in RTT mouse brain. Restored mitochondrial functionality was accompanied by the rescue of deficits in cognitive function (spatial reference memory in the Barnes maze), synaptic plasticity (long-term potentiation) and Tyr1472 phosphorylation of GluN2B, which was abnormally enhanced in the hippocampus of RTT mice. Present findings bring into light previously unknown functional mitochondrial alterations in the brain of female mice modeling RTT and provide the first evidence that RTT brain mitochondrial dysfunction can be rescued by modulation of Rho GTPases.
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http://dx.doi.org/10.1016/j.euroneuro.2015.03.012DOI Listing
June 2015

Cocaine-induced changes of synaptic transmission in the striatum are modulated by adenosine A2A receptors and involve the tyrosine phosphatase STEP.

Neuropsychopharmacology 2014 Feb 30;39(3):569-78. Epub 2013 Aug 30.

Department Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Roma, Italy.

The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum and mediate, at least in part, cocaine-induced psychomotor effects in vivo. Here we studied the synaptic mechanisms implicated in the pharmacological action of cocaine in the striatum and investigated the influence of A2ARs. We found that synaptic transmission was depressed in corticostriatal slices after perfusion with cocaine (10 μM). This effect was reduced by the A2AR antagonist ZM241385 and almost abolished in striatal A2AR-knockout mice (mice lacking A2ARs in striatal neurons, stA2ARKO). The effect of cocaine on synaptic transmission was also prevented by the protein tyrosine phosphatases (PTPs) inhibitor sodium orthovanadate (Na3VO4). In synaptosomes prepared from striatal slices, we found that the activity of striatal-enriched protein tyrosine phosphatase (STEP) was upregulated by cocaine, prevented by ZM241385, and absent in synaptosomes from stA2ARKO. The role played by STEP in cocaine modulation of synaptic transmission was investigated in whole-cell voltage clamp recordings from medium spiny neurons of the striatum. We found that TAT-STEP, a peptide that renders STEP enzymatically inactive, prevented cocaine-induced reduction in AMPA- and NMDA-mediated excitatory post-synaptic currents, whereas the control peptide, TAT-myc, had no effect. These results demonstrate that striatal A2ARs modulate cocaine-induced synaptic depression in the striatum and highlight the potential role of PTPs and specifically STEP in the effects of cocaine.
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http://dx.doi.org/10.1038/npp.2013.229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895235PMC
February 2014

BDNF prevents NMDA-induced toxicity in models of Huntington's disease: the effects are genotype specific and adenosine A2A receptor is involved.

J Neurochem 2013 Apr 27;125(2):225-35. Epub 2013 Feb 27.

Section of Central Nervous System Pharmacology, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.

NMDA receptor-mediated excitotoxicity is thought to play a pivotal role in the pathogenesis of Huntington's disease (HD). The neurotrophin brain-derived neurotrophic factor (BDNF), which is also highly involved in HD and whose effects are modulated by adenosine A2 ARs, influences the activity and expression of striatal NMDA receptors. In electrophysiology experiments, we investigated the role of BDNF toward NMDA-induced effects in HD models, and the possible involvement of A2ARs. In corticostriatal slices from wild-type mice and age-matched symptomatic R6/2 mice (a model of HD), NMDA application (75 μM) induced a transient or a permanent (i.e., toxic) reduction of field potential amplitude, respectively. BDNF (10 ng/mL) potentiated NMDA effects in wild-type, while it protected from NMDA toxicity in R6/2 mice. Both effects of BDNF were prevented by A2 AR blockade. The protective effect of BDNF against NMDA-induced toxicity was reproduced in a cellular model of HD. These findings may have very important implications for the neuroprotective potential of BDNF and A2 AR ligands in HD.
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http://dx.doi.org/10.1111/jnc.12177DOI Listing
April 2013

Unbalance of CB1 receptors expressed in GABAergic and glutamatergic neurons in a transgenic mouse model of Huntington's disease.

Neurobiol Dis 2012 Mar 23;45(3):983-91. Epub 2011 Dec 23.

Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

Cannabinoid CB1 receptors (CB1Rs) are known to be downregulated in patients and in animal models of Huntington's disease (HD). However, the functional meaning of this reduction, if any, is still unclear. Here, the effects of the cannabinoid receptor agonist WIN 55,212-2 (WIN) were investigated on striatal synaptic transmission and on glutamate and GABA release in symptomatic R6/2 mice, a genetic model of HD. The expression levels of CB1Rs in glutamatergic and GABAergic synapses were also evaluated. We found that in R6/2 mice, WIN effects on synaptic transmission and glutamate release were significantly increased with respect to wild type mice. On the contrary, a decrease in WIN-induced reduction of GABA release was found in R6/2 versus WT mice. The expression of CB1Rs in GABAergic neurons was drastically reduced, while CB1Rs levels in glutamatergic neurons were unchanged. These results demonstrate that the expression and functionality of CB1Rs are differentially affected in GABAergic and glutamatergic neurons in R6/2 mice. As a result, the balance between CB1Rs expressed by the two neuronal populations and, thus, the net effect of CB1R stimulation, is profoundly altered in HD mice.
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http://dx.doi.org/10.1016/j.nbd.2011.12.017DOI Listing
March 2012

Pre-synaptic adenosine A2A receptors control cannabinoid CB1 receptor-mediated inhibition of striatal glutamatergic neurotransmission.

J Neurochem 2011 Jan 2;116(2):273-80. Epub 2010 Dec 2.

Section of Central Nervous System Pharmacology, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.

An interaction between adenosine A(2A) receptors (A(2A) Rs) and cannabinoid CB(1) receptors (CB(1) Rs) has been consistently reported to occur in the striatum, although the precise mechanisms are not completely understood. As both receptors control striatal glutamatergic transmission, we now probed the putative interaction between pre-synaptic CB(1) R and A(2A) R in the striatum. In extracellular field potentials recordings in corticostriatal slices from Wistar rats, A(2A) R activation by CGS21680 inhibited CB(1) R-mediated effects (depression of synaptic response and increase in paired-pulse facilitation). Moreover, in superfused rat striatal nerve terminals, A(2A) R activation prevented, while A(2A) R inhibition facilitated, the CB(1) R-mediated inhibition of 4-aminopyridine-evoked glutamate release. In summary, the present study provides converging neurochemical and electrophysiological support for the occurrence of a tight control of CB(1) R function by A(2A) Rs in glutamatergic terminals of the striatum. In view of the key role of glutamate to trigger the recruitment of striatal circuits, this pre-synaptic interaction between CB(1) R and A(2A) R may be of relevance for the pathogenesis and the treatment of neuropsychiatric disorders affecting the basal ganglia.
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http://dx.doi.org/10.1111/j.1471-4159.2010.07101.xDOI Listing
January 2011

Role of adenosine A(2A) receptors in modulating synaptic functions and brain levels of BDNF: a possible key mechanism in the pathophysiology of Huntington's disease.

ScientificWorldJournal 2010 Sep 1;10:1768-82. Epub 2010 Sep 1.

Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome.

In the last few years, accumulating evidence has shown the existence of an important cross-talk between adenosine A(2A) receptors (A(2A)Rs) and brain-derived neurotrophic factor (BDNF). Not only are A(2A)Rs involved in the mechanism of transactivation of BDNF receptor TrkB, they also modulate the effect of BDNF on synaptic transmission, playing a facilitatory and permissive role. The cAMP-PKA pathway, the main transduction system operated by A(2A)Rs, is involved in such effects. Furthermore, a basal tonus of A(2A)Rs is required to allow the regulation of BDNF physiological levels in the brain, as demonstrated by the reduced protein levels measured in A(2A)Rs KO mice. The crucial role of adenosine A(2A)Rs in the maintenance of synaptic functions and BDNF levels will be reviewed here and discussed in the light of possible implications for Huntington's disease therapy, in which a joint impairment of BDNF and A(2A)Rs seems to play a pathogenetic role.
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http://dx.doi.org/10.1100/tsw.2010.164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763899PMC
September 2010

Influence of CGS 21680, a selective adenosine A(2A) receptor agonist, on NMDA receptor function and expression in the brain of Huntington's disease mice.

Brain Res 2010 Apr 4;1323:184-91. Epub 2010 Feb 4.

Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy.

The effect of chronic treatment with the selective adenosine A(2A) receptor agonist CGS 21680 on N-Methyl-d-Aspartate (NMDA) receptor function and expression has been studied in the striatum and cortex of R6/2 mice, a genetic mouse model of Huntington's disease (HD). Starting from 8weeks of age, R6/2 and wild type (WT) mice were treated daily with CGS 21680 (0.5mg/kg i.p.) for 3weeks and the expression levels of NMDA receptor subunits were then evaluated. In addition, to study CGS 21680-induced changes in NMDA receptor function, NMDA-induced toxicity in corticostriatal slices from both R6/2 and WT mice was investigated. We found that CGS 21680 increased NR2A subunit expression and the NR2A/NR2B ratio in the cortex of R6/2 mice, having no effect in WT mice. In the striatum, CGS 21680 reduced NR1 expression in both R6/2 and WT mice while the effect on NR2A and NR2/NR2B expression was genotype-dependent, reducing and increasing their expression in WT and R6/2 mice, respectively. On the contrary, NMDA-induced toxicity in corticostriatal slices was not modified by the treatment in WT or HD mice. These results demonstrate that in vivo activation of A(2A) receptors modulates the subunit composition of NMDA receptors in the brain of HD mice.
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http://dx.doi.org/10.1016/j.brainres.2010.01.080DOI Listing
April 2010

Adenosine A2A receptors enable the synaptic effects of cannabinoid CB1 receptors in the rodent striatum.

J Neurochem 2009 Sep 17;110(6):1921-30. Epub 2009 Jul 17.

Section of Central Nervous System Pharmacology, Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.

Adenosine A(2A), cannabinoid CB(1) and metabotropic glutamate 5 (mGlu(5)) receptors are all highly expressed in the striatum. The aim of the present work was to investigate whether, and by which mechanisms, the above receptors interact in the regulation of striatal synaptic transmission. By extracellular field potentials (FPs) recordings in corticostriatal slices, we demonstrated that the ability of the selective type 1 cannabinoid receptor (CB(1)R) agonist WIN55,212-2 to depress synaptic transmission was prevented by the pharmacological blockade or the genetic inactivation of A(2A)Rs. Such a permissive effect of A(2A)Rs towards CB(1)Rs does not seem to occur pre-synaptically as the ability of WIN55,212-2 to increase the R2/R1 ratio under a protocol of paired-pulse stimulation was not modified by ZM241385. Furthermore, the effects of WIN55,212-2 were reduced in slices from mice lacking post-synaptic striatal A(2A)Rs. The selective mGlu(5)R agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) potentiated the synaptic effects of WIN55,212-2, and such a potentiation was abolished by A(2A)R blockade. Unlike the synaptic effects, the ability of WIN55,212-2 to prevent NMDA-induced toxicity was not influenced by ZM241385. Altogether, these results show that the state of activation of A(2A)Rs regulates the synaptic effects of CB(1)Rs and that A(2A)Rs may control CB(1) effects also indirectly, namely through mGlu(5)Rs.
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http://dx.doi.org/10.1111/j.1471-4159.2009.06282.xDOI Listing
September 2009

Prenatal restraint stress generates two distinct behavioral and neurochemical profiles in male and female rats.

PLoS One 2008 May 14;3(5):e2170. Epub 2008 May 14.

Perinatal Stress Lab., University Lille 1, Villeneuve d'Ascq, France.

Prenatal Restraint Stress (PRS) in rats is a validated model of early stress resulting in permanent behavioral and neurobiological outcomes. Although sexual dimorphism in the effects of PRS has been hypothesized for more than 30 years, few studies in this long period have directly addressed the issue. Our group has uncovered a pronounced gender difference in the effects of PRS (stress delivered to the mothers 3 times per day during the last 10 days of pregnancy) on anxiety, spatial learning, and a series of neurobiological parameters classically associated with hippocampus-dependent behaviors. Adult male rats subjected to PRS ("PRS rats") showed increased anxiety-like behavior in the elevated plus maze (EPM), a reduction in the survival of newborn cells in the dentate gyrus, a reduction in the activity of mGlu1/5 metabotropic glutamate receptors in the ventral hippocampus, and an increase in the levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF in the hippocampus. In contrast, female PRS rats displayed reduced anxiety in the EPM, improved learning in the Morris water maze, an increase in the activity of mGlu1/5 receptors in the ventral and dorsal hippocampus, and no changes in hippocampal neurogenesis or BDNF levels. The direction of the changes in neurogenesis, BDNF levels and mGlu receptor function in PRS animals was not consistent with the behavioral changes, suggesting that PRS perturbs the interdependency of these particular parameters and their relation to hippocampus-dependent behavior. Our data suggest that the epigenetic changes in hippocampal neuroplasticity induced by early environmental challenges are critically sex-dependent and that the behavioral outcome may diverge in males and females.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002170PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2366064PMC
May 2008

Neurobehavioral assessment of rats exposed to low doses of PCB126 and methyl mercury during development.

Environ Toxicol Pharmacol 2008 Jan 26;25(1):103-13. Epub 2007 Sep 26.

Department of Human Anatomy, Pharmacology and Forensic Sciences, University of Parma Medical School, Parma, Via Volturno 39, 43100 Parma, Italy.

Epidemiological and laboratory studies have suggested that polychlorinated biphenyls (PCBs) and methyl mercury (MeHg) may have additive or synergistic effects on CNS function. Aim of this study was to characterize the effects of exposure to low levels of MeHg (0.5mg/kgday in drinking water) and PCB126 (100ng/kgday in food), alone and in combination, on neurobehavioral development in Wistar rats. Dams were treated from gestational day 7 to post-natal day (PND) 21. Animals were tested for developmental landmarks and reflexes (PND1-21), attention deficits (PND40), locomotor activity (PND30, 110), spatial learning (PND75), coordination and balance (PND90), object discrimination (PND80), anxiety (PND100), and conditioned learning (PND110). Parameters related to pregnancy, sex ratio at birth, and physical development (at weaning) did not differ among groups, though PCB126 decreased number of pups at birth. A slight delay in negative geotaxis was found in female rats in all treatment groups. No significant effects were seen in attention, coordination and balance, object discrimination, and spatial and conditioned learning. Increased motor activity was present in PCB126-treated male and in MeHg+PCB-treated female rats in the elevated plus maze test, and in PCB126-treated male rats in the open field test (PND110). The results do not support the hypothesis that co-exposure to MeHg and PCB126 results in additive or synergistic effects. This finding is in agreement with more recent in vitro and in vivo studies.
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http://dx.doi.org/10.1016/j.etap.2007.09.006DOI Listing
January 2008

Maternal exposure to low levels of corticosterone during lactation protects the adult offspring against ischemic brain damage.

J Neurosci 2007 Jun;27(26):7041-6

Department of Human Physiology and Pharmacology, University of Rome La Sapienza, Faculty of Medicine, 00185 Rome, Italy.

A growing body of evidence underscores the importance of early life events as predictors of health in adulthood. Abnormalities in maternal care or other forms of early postnatal stress induce long-term changes in behavior and influence the vulnerability to illnesses throughout life. Some of these changes may be produced by the activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is invariably associated with stress. We used a model in which neonate rats are fed by mothers drinking water supplemented with 0.2 mg/ml corticosterone, the main glucocorticoid hormone in rodents. Plasma corticosterone levels increased in the dams to an extent similar to that induced by a mild stress. Corticosterone-treated dams also showed an increase in maternal care. Remarkably, adult rats that had been nursed by corticosterone-treated mothers were protected against neuronal damage and cognitive impairment produced by transient global brain ischemia. Neuroprotection was associated with a reduced HPA response to ischemia and was primarily decreased when corticosterone was injected at a dose that eliminated any difference in endogenous corticosterone levels between rats raised by mothers supplemented with corticosterone and their matched controls. These data suggest that an increased maternal care protects the offspring against ischemic neuronal damage and that at least a component of neuroprotection is mediated by a reduced response of the HPA axis to ischemia.
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http://dx.doi.org/10.1523/JNEUROSCI.1074-07.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672222PMC
June 2007