Publications by authors named "Giuseppe Sciamanna"

29 Publications

  • Page 1 of 1

Facemasks and face recognition: Potential impact on synaptic plasticity.

Neurobiol Dis 2021 06 26;153:105319. Epub 2021 Feb 26.

Department of Clinical Science and Translational Medicine, University of Rome Tor Vergata, Rome, Italy.

Visual recognition of facial expression modulates our social interactions. Compelling experimental evidence indicates that face conveys plenty of information that are fundamental for humans to interact. These are encoded at neural level in specific cortical and subcortical brain regions through activity- and experience-dependent synaptic plasticity processes. The current pandemic, due to the spread of SARS-CoV-2 infection, is causing relevant social and psychological detrimental effects. The institutional recommendations on physical distancing, namely social distancing and wearing of facemasks are effective in reducing the rate of viral spread. However, by impacting social interaction, facemasks might impair the neural responses to recognition of facial cues that are overall critical to our behaviors. In this survey, we briefly review the current knowledge on the neurobiological substrate of facial recognition and discuss how the lack of salient stimuli might impact the ability to retain and consolidate learning and memory phenomena underlying face recognition. Such an "abnormal" visual experience raises the intriguing possibility of a "reset" mechanism, a renewed ability of adult brain to undergo synaptic plasticity adaptations.
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http://dx.doi.org/10.1016/j.nbd.2021.105319DOI Listing
June 2021

Optogenetic Stimulation of Prelimbic Pyramidal Neurons Maintains Fear Memories and Modulates Amygdala Pyramidal Neuron Transcriptome.

Int J Mol Sci 2021 Jan 15;22(2). Epub 2021 Jan 15.

Department of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy.

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.
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http://dx.doi.org/10.3390/ijms22020810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830910PMC
January 2021

Optogenetic Activation of Striatopallidal Neurons Reveals Altered HCN Gating in DYT1 Dystonia.

Cell Rep 2020 05;31(7):107644

Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy; Lab of Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy. Electronic address:

Firing activity of external globus pallidus (GPe) is crucial for motor control and is severely perturbed in dystonia, a movement disorder characterized by involuntary, repetitive muscle contractions. Here, we show that GPe projection neurons exhibit a reduction of firing frequency and an irregular pattern in a DYT1 dystonia model. Optogenetic activation of the striatopallidal pathway fails to reset pacemaking activity of GPe neurons in mutant mice. Abnormal firing is paralleled by alterations in motor learning. We find that loss of dopamine D2 receptor-dependent inhibition causes increased GABA input at striatopallidal synapses, with subsequent downregulation of hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. Accordingly, enhancing in vivo HCN channel activity or blocking GABA release restores both the ability of striatopallidal inputs to pause ongoing GPe activity and motor coordination deficits. Our findings demonstrate an impaired striatopallidal connectivity, supporting the central role of GPe in motor control and, more importantly, identifying potential pharmacological targets for dystonia.
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http://dx.doi.org/10.1016/j.celrep.2020.107644DOI Listing
May 2020

Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia.

Neurobiol Dis 2020 02 31;134:104634. Epub 2019 Oct 31.

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany; Department of Human Genetics, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany. Electronic address:

Dystonia is a neurological movement disorder characterized by sustained or intermittent involuntary muscle contractions. Loss-of-function mutations in the GNAL gene have been identified to be the cause of "isolated" dystonia DYT25. The GNAL gene encodes for the guanine nucleotide-binding protein G(olf) subunit alpha (Gα), which is mainly expressed in the olfactory bulb and the striatum and functions as a modulator during neurotransmission coupling with D1R and A2AR. Previously, heterozygous Gα -deficient mice (Gnal) have been generated and showed a mild phenotype at basal condition. In contrast, homozygous deletion of Gnal in mice (Gnal) resulted in a significantly reduced survival rate. In this study, using the CRISPR-Cas9 system we generated and characterized heterozygous Gnal knockout rats (Gnal) with a 13 base pair deletion in the first exon of the rat Gnal splicing variant 2, a major isoform in both human and rat striatum. Gnal rats showed early-onset phenotypes associated with impaired dopamine transmission, including reduction in locomotor activity, deficits in rotarod performance and an abnormal motor skill learning ability. At cellular and molecular level, we found down-regulated Arc expression, increased cell surface distribution of AMPA receptors, and the loss of D2R-dependent corticostriatal long-term depression (LTD) in Gnal rats. Based on the evidence that D2R activity is normally inhibited by adenosine A2ARs, co-localized on the same population of striatal neurons, we show that blockade of A2ARs restores physiological LTD. This animal model may be a valuable tool for investigating Gα function and finding a suitable treatment for dystonia associated with deficient dopamine transmission.
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http://dx.doi.org/10.1016/j.nbd.2019.104634DOI Listing
February 2020

RGS9-2 rescues dopamine D2 receptor levels and signaling in dystonia mouse models.

EMBO Mol Med 2019 01;11(1)

Laboratory of Neurophysiology and Plasticity, IRCCS Fondazione Santa Lucia, Rome, Italy

Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early-onset 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 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 dystonia striatum, whereas RGS9-2 overexpression rescues both receptor levels and electrophysiological responses in striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in mice and in turn explains why dopaminergic drugs lack efficacy in 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.
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http://dx.doi.org/10.15252/emmm.201809283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328939PMC
January 2019

Dystonia as a network disorder: a concept in evolution.

Curr Opin Neurol 2018 08;31(4):498-503

Department of Systems Medicine, University of Roma Tor Vergata.

Purpose Of Review: This survey takes into consideration the most recent advances in both human degenerative ataxias, disorders with a well established cerebellar origin, and discoveries from dystonia rodent models aimed at discussing the pathogenesis of dystonia.

Recent Findings: One common recurrent term that emerges when describing dystonia is heterogeneity. Indeed, dystonia encompasses a wide group of 'hyperkinetic' movement disorders, with heterogeneous causes, classification, anatomical and physiological substrates. In addition, the clinical heterogeneity of age at onset, symptom distribution and appearance of non-motor symptoms has supported the concept of dystonia as 'network' disorder. Pathophysiological alterations are thought to arise from dysfunction at cortico-thalamic-basal ganglia level, whereas, more recently, a role for cerebellar pathways emerged. Results from human and animal studies thus fuel the evolving concept of the network disorder.

Summary: Current evidence suggests the involvement of multiple brain regions and cellular mechanisms, as part of the neural dysfunction observed at system level in dystonia.
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http://dx.doi.org/10.1097/WCO.0000000000000580DOI Listing
August 2018

Early structural and functional plasticity alterations in a susceptibility period of DYT1 dystonia mouse striatum.

Elife 2018 03 5;7. Epub 2018 Mar 5.

Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

The onset of abnormal movements in DYT1 dystonia is between childhood and adolescence, although it is unclear why clinical manifestations appear during this developmental period. Plasticity at corticostriatal synapses is critically involved in motor memory. In the DYT1 dystonia mouse model, long-term potentiation (LTP) appeared prematurely in a critical developmental window in striatal spiny neurons (SPNs), while long-term depression (LTD) was never recorded. Analysis of dendritic spines showed an increase of both spine width and mature mushroom spines in neurons, paralleled by an enhanced AMPA receptor (AMPAR) accumulation. BDNF regulates AMPAR expression during development. Accordingly, both proBDNF and BDNF levels were significantly higher in mice. Consistently, antagonism of BDNF rescued synaptic plasticity deficits and AMPA currents. Our findings demonstrate that early loss of functional and structural synaptic homeostasis represents a unique endophenotypic trait during striatal maturation, promoting the appearance of clinical manifestations in mutation carriers.
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http://dx.doi.org/10.7554/eLife.33331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849413PMC
March 2018

Enhanced mu opioid receptor-dependent opioidergic modulation of striatal cholinergic transmission in DYT1 dystonia.

Mov Disord 2018 02 18;33(2):310-320. Epub 2017 Nov 18.

Department of Systems Medicine, University of Rome "Tor Vergata,", Rome, Italy.

Background: Mu opioid receptor activation modulates acetylcholine release in the dorsal striatum, an area deeply involved in motor function, habit formation, and reinforcement learning as well as in the pathophysiology of different movement disorders, such as dystonia. Although the role of opioids in drug reward and addiction is well established, their involvement in motor dysfunction remains largely unexplored.

Methods: We used a multidisciplinary approach to investigate the responses to mu activation in 2 mouse models of DYT1 dystonia (Tor1a mice, Tor1a torsinA null mice, and their respective wild-types). We performed electrophysiological recordings to characterize the pharmacological effects of receptor activation in cholinergic interneurons as well as the underlying ionic currents. In addition, an analysis of the receptor expression was performed both at the protein and mRNA level.

Results: In mutant mice, selective mu receptor activation caused a stronger G-protein-dependent, dose-dependent inhibition of firing activity in cholinergic interneurons when compared with controls. In Tor1a mice, our electrophysiological analysis showed an abnormal involvement of calcium-activated potassium channels. Moreover, in both models we found increased levels of mu receptor protein. In addition, both total mRNA and the mu opioid receptor splice variant 1S (MOR-1S) splice variant of the mu receptor gene transcript, specifically enriched in striatum, were selectively upregulated.

Conclusion: Mice with the DYT1 dystonia mutation exhibit an enhanced response to mu receptor activation, dependent on selective receptor gene upregulation. Our data suggest a novel role for striatal opioid signaling in motor control, and more important, identify mu opioid receptors as potential targets for pharmacological intervention in dystonia. © 2017 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27212DOI Listing
February 2018

Promising rodent models in Parkinson's disease.

Parkinsonism Relat Disord 2018 Jan 27;46 Suppl 1:S10-S14. Epub 2017 Jul 27.

Neurology, Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy; Fondazione Santa Lucia I.R.C.C.S., Laboratory of Neurophysiology and Plasticity, Rome, Italy. Electronic address:

Background: In the past decade, the study of the pathogenic mechanisms underlying neurodegeneration in Parkinson's disease (PD) has revealed a genetic component, often associated with a number of environmental risk factors. Animal models have improved our understanding of disease pathogenesis, providing significant insights into the understanding of novel molecular pathways. Each model has its own specific features and limitations, and the choice of the most appropriate one depends on the specific question that has to be answered.

Aim: To provide an overview of some of the models supporting the hypothesis that early synaptic dysfunction represents a central event in the course of the disease.

Development: Along with "classical" models, based on the administration of neurotoxins and capable of replicating the neuropathological hallmarks of the disease, a number of genetic models, reproducing the disease-causing mutations of monogenic forms of familial PD, have been generated. More recently, novel models have been developed, based on the combination of a toxic insult together with PD mutations, allowing for the identification of dysfunction at a prodromal disease stage.

Conclusions: The development and characterization of new models is crucial for a better understanding of PD related-synaptopathy, and hold promise for the identification of novel therapeutics.
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http://dx.doi.org/10.1016/j.parkreldis.2017.07.027DOI Listing
January 2018

Optogenetic stimulation reveals distinct modulatory properties of thalamostriatal vs corticostriatal glutamatergic inputs to fast-spiking interneurons.

Sci Rep 2015 Nov 17;5:16742. Epub 2015 Nov 17.

University of Rome "Tor Vergata", Dept. of Systems Medicine, via Montpellier 1 -00133, Rome.

Parvalbumin-containing fast-spiking interneurons (FSIs) exert a powerful feed-forward GABAergic inhibition on striatal medium spiny neurons (MSNs), playing a critical role in timing striatal output. However, how glutamatergic inputs modulate their firing activity is still unexplored. Here, by means of a combined optogenetic and electrophysiological approach, we provide evidence for a differential modulation of cortico- vs thalamo-striatal synaptic inputs to FSIs in transgenic mice carrying light-gated ion channels channelrhodopsin-2 (ChR2) in glutamatergic fibers. Corticostriatal synapses show a postsynaptic facilitation, whereas thalamostriatal synapses present a postsynaptic depression. Moreover, thalamostriatal synapses exhibit more prominent AMPA-mediated currents than corticostriatal synapses, and an increased release probability. Furthermore, during current-evoked firing activity, simultaneous corticostriatal stimulation increases bursting activity. Conversely, thalamostriatal fiber activation shifts the canonical burst-pause activity to a more prolonged, regular firing pattern. However, this change in firing pattern was accompanied by a significant rise in the frequency of membrane potential oscillations. Notably, the responses to thalamic stimulation were fully abolished by blocking metabotropic glutamate 1 (mGlu1) receptor subtype, whereas both acetylcholine and dopamine receptor antagonists were ineffective. Our findings demonstrate that cortical and thalamic glutamatergic input differently modulate FSIs firing activity through specific intrinsic and synaptic properties, exerting a powerful influence on striatal outputs.
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http://dx.doi.org/10.1038/srep16742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647205PMC
November 2015

Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion.

Sci Rep 2015 Jul 20;5:10933. Epub 2015 Jul 20.

CEINGE Biotecnologie Avanzate, Naples, Italy.

Mechanisms of gender-specific synaptic plasticity in the striatum, a brain region that controls motor, cognitive and psychiatric functions, remain unclear. Here we report that Rhes, a GTPase enriched in medium spiny neurons (MSNs) of striatum, alters the striatal cAMP/PKA signaling cascade in a gender-specific manner. While Rhes knockout (KO) male mice, compared to wild-type (WT) mice, had a significant basal increase of cAMP/PKA signaling pathway, the Rhes KO females exhibited a much stronger response of this pathway, selectively under the conditions of dopamine/adenosine-related drug challenge. Corticostriatal LTP defects are exclusively found in A2AR/D2R-expressing MSNs of KO females, compared to KO males, an effect that is abolished by PKA inhibitors but not by the removal of circulating estrogens. This suggests that the synaptic alterations found in KO females could be triggered by an aberrant A2AR/cAMP/PKA activity, but not due to estrogen-mediated effect. Consistent with increased cAMP signaling, D1R-mediated motor stimulation, haloperidol-induced catalepsy and caffeine-evoked hyper-activity are robustly enhanced in Rhes KO females compared to mutant males. Thus Rhes, a thyroid hormone-target gene, plays a relevant role in gender-specific synaptic and behavioral responses.
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http://dx.doi.org/10.1038/srep10933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507147PMC
July 2015

Rhes regulates dopamine D2 receptor transmission in striatal cholinergic interneurons.

Neurobiol Dis 2015 Jun 26;78:146-61. Epub 2015 Mar 26.

CEINGE Biotecnologie Avanzate, Via G. Salvatore 486, 80145 Naples, Italy; Department of Environmental Sciences, Second University of Naples (SUN), Via Vivaldi 43, 81100 Caserta, Italy. Electronic address:

Ras homolog enriched in striatum (Rhes) is highly expressed in striatal medium spiny neurons (MSNs) of rodents. In the present study, we characterized the expression of Rhes mRNA across species, as well as its functional role in other striatal neuron subtypes. Double in situ hybridization analysis showed that Rhes transcript is selectively localized in striatal cholinergic interneurons (ChIs), but not in GABAergic parvalbumin- or in neuropeptide Y-positive cell populations. Rhes is closely linked to dopamine-dependent signaling. Therefore, we recorded ChIs activity in basal condition and following dopamine receptor activation. Surprisingly, instead of an expected dopamine D2 receptor (D2R)-mediated inhibition, we observed an aberrant excitatory response in ChIs from Rhes knockout mice. Conversely, the effect of D1R agonist on ChIs was less robust in Rhes mutants than in controls. Although Rhes deletion in mutants occurs throughout the striatum, we demonstrate that the D2R response is altered specifically in ChIs, since it was recorded in pharmacological isolation, and prevented either by intrapipette BAPTA or by GDP-β-S. Moreover, we show that blockade of Cav2.2 calcium channels prevented the abnormal D2R response. Finally, we found that the abnormal D2R activation in ChIs was rescued by selective PI3K inhibition thus suggesting that Rhes functionally modulates PI3K/Akt signaling pathway in these neurons. Our findings reveal that, besides its expression in MSNs, Rhes is localized also in striatal ChIs and, most importantly, lack of this G-protein, significantly alters D2R modulation of striatal cholinergic excitability.
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http://dx.doi.org/10.1016/j.nbd.2015.03.021DOI Listing
June 2015

Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors.

Mov Disord 2014 Nov 4;29(13):1655-65. Epub 2014 Sep 4.

Department of Systems Medicine, University of Rome "Tor Vergata", Italy; IRCCS Fondazione Santa Lucia, Rome, Italy.

Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a(+/Δgag) ) mice heterozygous for ΔE-torsinA and their controls (Tor1a(+/+) mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a(+/Δgag) mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1 -preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1 -dependent potentiation of N-methyl-d-aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder.
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http://dx.doi.org/10.1002/mds.26009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4216601PMC
November 2014

Torsin A Localization in the Mouse Cerebellar Synaptic Circuitry.

PLoS One 2013 19;8(6):e68063. Epub 2013 Jun 19.

Department of Systems Medicine, University of Rome Tor Vergata/Laboratory of Neurophysiology and Synaptic Plasticity, Fondazione Santa Lucia, Rome, Italy.

Torsin A (TA) is a ubiquitous protein belonging to the superfamily of proteins called "ATPases associated with a variety of cellular activities" (AAA(+) ATPase). To date, a great deal of attention has been focused on neuronal TA since its mutant form causes early-onset (DYT1) torsion dystonia, an inherited movement disorder characterized by sustained muscle contractions and abnormal postures. Interestingly, it has been proposed that TA, by interacting with the cytoskeletal network, may contribute to the control of neurite outgrowth and/or by acting as a chaperone at synapses could affect synaptic vesicle turnover and neurotransmitter release. Accordingly, both its peculiar developmental expression in striatum and cerebellum and evidence from DYT1 knock-in mice suggest that TA may influence dendritic arborization and synaptogenesis in the brain. Therefore, to better understand TA function a detailed description of its localization at synaptic level is required. Here, we characterized by means of rigorous quantitative confocal analysis TA distribution in the mouse cerebellum at postnatal day 14 (P14), when both cerebellar synaptogenesis and TA expression peak. We observed that the protein is broadly distributed both in cerebellar cortex and in the deep cerebellar nuclei (DCN). Of note, Purkinje cells (PC) express high levels of TA also in the spines and axonal terminals. In addition, abundant expression of the protein was found in the main GABA-ergic and glutamatergic inputs of the cerebellar cortex. Finally, TA was observed also in glial cells, a cellular population little explored so far. These results extend our knowledge on TA synaptic localization providing a clue to its potential role in synaptic development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0068063PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686744PMC
October 2017

Cholinergic dysfunction alters synaptic integration between thalamostriatal and corticostriatal inputs in DYT1 dystonia.

J Neurosci 2012 Aug;32(35):11991-2004

Department of Neuroscience, University Tor Vergata/Laboratory of Neurophysiology and Synaptic Plasticity, Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico, 00143 Rome, Italy.

Projections from thalamic intralaminar nuclei convey sensory signals to striatal cholinergic interneurons. These neurons respond with a pause in their pacemaking activity, enabling synaptic integration with cortical inputs to medium spiny neurons (MSNs), thus playing a crucial role in motor function. In mice with the DYT1 dystonia mutation, stimulation of thalamostriatal axons, mimicking a response to salient events, evoked a shortened pause and triggered an abnormal spiking activity in interneurons. This altered pattern caused a significant rearrangement of the temporal sequence of synaptic activity mediated by M(1) and M(2) muscarinic receptors in MSNs, consisting of an increase in postsynaptic currents and a decrease of presynaptic inhibition, respectively. Consistent with a major role of acetylcholine, either lowering cholinergic tone or antagonizing postsynaptic M(1) muscarinic receptors normalized synaptic activity. Our data demonstrate an abnormal time window for synaptic integration between thalamostriatal and corticostriatal inputs, which might alter the action selection process, thereby predisposing DYT1 gene mutation carriers to develop dystonic movements.
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http://dx.doi.org/10.1523/JNEUROSCI.0041-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471539PMC
August 2012

Cholinergic dysregulation produced by selective inactivation of the dystonia-associated protein torsinA.

Neurobiol Dis 2012 Sep 3;47(3):416-27. Epub 2012 May 3.

Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata and Fondazione Santa Lucia, I.R.C.C.S., Rome, Italy.

DYT1 dystonia, a common and severe primary dystonia, is caused by a 3-bp deletion in TOR1A which encodes torsinA, a protein found in the endoplasmic reticulum. Several cellular functions are altered by the mutant protein, but at a systems level the link between these and the symptoms of the disease is unclear. The most effective known therapy for DYT1 dystonia is the use of anticholinergic drugs. Previous studies have revealed that in mice, transgenic expression of human mutant torsinA under a non-selective promoter leads to abnormal function of striatal cholinergic neurons. To investigate what pathological role torsinA plays in cholinergic neurons, we created a mouse model in which the Dyt1 gene, the mouse homolog of TOR1A, is selectively deleted in cholinergic neurons (ChKO animals). These animals do not have overt dystonia, but do have subtle motor abnormalities. There is no change in the number or size of striatal cholinergic cells or striatal acetylcholine content, uptake, synthesis, or release in ChKO mice. There are, however, striking functional abnormalities of striatal cholinergic cells, with paradoxical excitation in response to D2 receptor activation and loss of muscarinic M2/M4 receptor inhibitory function. These effects are specific for cholinergic interneurons, as recordings from nigral dopaminergic neurons revealed normal responses. Amphetamine stimulated dopamine release was also unaltered. These results demonstrate a cell-autonomous effect of Dyt1 deletion on striatal cholinergic function. Therapies directed at modifying the function of cholinergic neurons may prove useful in the treatment of the human disorder.
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http://dx.doi.org/10.1016/j.nbd.2012.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392411PMC
September 2012

Generation of a novel rodent model for DYT1 dystonia.

Neurobiol Dis 2012 Jul 26;47(1):61-74. Epub 2012 Mar 26.

Dept. of Medical Genetics, University of Tuebingen, Germany.

A mutation in the coding region of the Tor1A gene, resulting in a deletion of a glutamic acid residue in the torsinA protein (∆ETorA), is the major cause of the inherited autosomal-dominant early onset torsion dystonia (DYT1). The pathophysiological consequences of this amino acid loss are still not understood. Currently available animal models for DYT1 dystonia provided important insights into the disease; however, they differ with respect to key features of torsinA associated pathology. We developed transgenic rat models harboring the full length human mutant and wildtype Tor1A gene. A complex phenotyping approach including classical behavioral tests, electrophysiology and neuropathology revealed a progressive neurological phenotype in ∆ETorA expressing rats. Furthermore, we were able to replicate key pathological features of torsinA associated pathology in a second species, such as nuclear envelope pathology, behavioral abnormalities and plasticity changes. We therefore suggest that this rat model represents an appropriate new model suitable to further investigate the pathophysiology of ∆ETorA and to test for therapeutic approaches.
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http://dx.doi.org/10.1016/j.nbd.2012.03.024DOI Listing
July 2012

Developmental profile of the aberrant dopamine D2 receptor response in striatal cholinergic interneurons in DYT1 dystonia.

PLoS One 2011 2;6(9):e24261. Epub 2011 Sep 2.

Department of Neuroscience, University Tor Vergata, Rome, Italy.

Background: DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear.

Methods And Results: We characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT). An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon G-proteins, as it was prevented by intrapipette GDP-β-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calcium abolished the paradoxical response to quinpirole. Finally, no gross morphological changes were observed during development.

Conclusions: These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystonia and persists along development, representing a susceptibility factor for symptom generation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024261PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166312PMC
December 2011

Experimental models of dystonia.

Int Rev Neurobiol 2011 ;98:551-72

Department of Neuroscience, University Tor Vergata, Rome, Italy.

Dystonia is a disabling movement disorder characterized by involuntary, sustained muscle contractions, with repetitive twisting movements and abnormal postures. It is clinically classified as primary, either sporadic or genetic, or secondary, following focal brain lesions. The recent past has witnessed remarkable progress in finding genes for dystonia. However, translating the findings from genetics into concrete changes for dystonic patients is not immediate, as it requires extensive exploration of the consequences of gene defects on motor behavior, protein biochemistry, and cell physiology. Thus, in the last decade, a number of animal models have been generated and, to some extent, characterized. These include distinct species, ranging from invertebrates, such as Caenorhabditis elegans and Drosophila melanogaster, to rodents and nonhuman primates. The mouse is the average choice of mammalian models in most laboratories, particularly when manipulations of the genome are planned. Investigations of animals provide results that do not always reproduce the clinical features of human dystonia. Indeed, most of the mouse models of inherited dystonia do not exhibit overt dystonia although they do have subtle motor abnormalities and well-characterized neurochemical and neurophysiological alterations. Conversely, spontaneous mutant models display a clear phenotype, but in some cases the origin of the mutation is unknown. In spite of such limitations and apparent contradictory evidence, there is general consensus on the notion that a useful animal model has to be judged by how reliably and effectively it can be used to explore novel aspects of pathophysiology and potential treatments. In the present work, we briefly describe the most commonly utilized models for the study of dystonia and the results obtained, in attempt to provide a comprehensive overview of the current, available models.
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http://dx.doi.org/10.1016/B978-0-12-381328-2.00020-1DOI Listing
January 2012

The ionic mechanism of gamma resonance in rat striatal fast-spiking neurons.

J Neurophysiol 2011 Dec 31;106(6):2936-49. Epub 2011 Aug 31.

Laboratory of Neurophysiology and Plasticity, Santa Lucia Foundation IRCCS, Rome, Italy.

Striatal fast-spiking (FS) cells in slices fire in the gamma frequency range and in vivo are often phase-locked to gamma oscillations in the field potential. We studied the firing patterns of these cells in slices from rats ages 16-23 days to determine the mechanism of their gamma resonance. The resonance of striatal FS cells was manifested as a minimum frequency for repetitive firing. At rheobase, cells fired a doublet of action potentials or doublets separated by pauses, with an instantaneous firing rate averaging 44 spikes/s. The minimum rate for sustained firing was also responsible for the stuttering firing pattern. Firing rate adapted during each episode of firing, and bursts were terminated when firing was reduced to the minimum sustainable rate. Resonance and stuttering continued after blockade of Kv3 current using tetraethylammonium (0.1-1 mM). Both gamma resonance and stuttering were strongly dependent on Kv1 current. Blockade of Kv1 channels with dendrotoxin-I (100 nM) completely abolished the stuttering firing pattern, greatly lowered the minimum firing rate, abolished gamma-band subthreshold oscillations, and slowed spike frequency adaptation. The loss of resonance could be accounted for by a reduction in potassium current near spike threshold and the emergence of a fixed spike threshold. Inactivation of the Kv1 channel combined with the minimum firing rate could account for the stuttering firing pattern. The resonant properties conferred by this channel were shown to be adequate to account for their phase-locking to gamma-frequency inputs as seen in vivo.
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http://dx.doi.org/10.1152/jn.00280.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234086PMC
December 2011

Homeostatic changes of the endocannabinoid system in Parkinson's disease.

Mov Disord 2011 Feb 13;26(2):216-22. Epub 2010 Dec 13.

Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy.

Endocannabinoids (eCBs) are endogenous lipids that bind principally type-1 and type-2 cannabinoid (CB(1) and CB(2)) receptors. N-Arachidonoylethanolamine (AEA, anandamide) and 2-arachidonoylglycerol (2-AG) are the best characterized eCBs that are released from membrane phospholipid precursors through multiple biosynthetic pathways. Together with their receptors and metabolic enzymes, eCBs form the so-called "eCB system". The later has been involved in a wide variety of actions, including modulation of basal ganglia function. Consistently, both eCB levels and CB(1) receptor expression are high in several basal ganglia regions, and more specifically in the striatum and in its target projection areas. In these regions, the eCB system establishes a close functional interaction with dopaminergic neurotransmission, supporting a relevant role for eCBs in the control of voluntary movements. Accordingly, compelling experimental and clinical evidence suggests that a profound rearrangement of the eCB system in the basal ganglia follows dopamine depletion, as it occurs in Parkinson's disease (PD). In this article, we provide a brief survey of the evidence that the eCB system changes in both animal models of, and patients suffering from, PD. A striking convergence of findings is observed between both rodent and primate models and PD patients, indicating that the eCB system undergoes dynamic, adaptive changes, aimed at restoring an apparent homeostasis within the basal ganglia network.
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http://dx.doi.org/10.1002/mds.23457DOI Listing
February 2011

Electrophysiology of 5-HT6 receptors.

Int Rev Neurobiol 2010 ;94:111-28

Laboratory of Neurophysiology and Plasticity, I.R.C.C.S. Fondazione Santa Lucia, Rome, Italy.

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http://dx.doi.org/10.1016/B978-0-12-384976-2.00005-8DOI Listing
September 2011

Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia.

Neurobiol Dis 2010 Jun 19;38(3):434-45. Epub 2010 Mar 19.

CEINGE Biotecnologie Avanzate, Naples, Italy.

DYT1 dystonia is an inherited disease linked to mutation in the TOR1A gene encoding for the protein torsinA. Although the mechanism by which this genetic alteration leads to dystonia is unclear, multiple lines of clinical evidence suggest a link between dystonia and a reduced dopamine D2 receptor (D2R) availability. Based on this evidence, herein we carried out a comprehensive analysis of electrophysiological, behavioral and signaling correlates of D2R transmission in transgenic mice with the DYT1 dystonia mutation. Electrophysiological recordings from nigral dopaminergic neurons showed a normal responsiveness to D2-autoreceptor function. Conversely, postsynaptic D2R function in hMT mice was impaired, as suggested by the inability of a D2R agonist to re-establish normal corticostriatal synaptic plasticity and supported by the reduced sensitivity to haloperidol-induced catalepsy. Although an in situ hybridization analysis showed normal D1R and D2R mRNA expression levels in the striata of hMT mice, we found a significant decrease of D2R protein, coupled to a reduced ability of D2Rs to activate their cognate Go/i proteins. Of relevance, we found that pharmacological blockade of adenosine A2A receptors (A2ARs) fully restored the impairment of synaptic plasticity observed in hMT mice. Together, our findings demonstrate an important link between torsinA mutation and D2R dysfunction and suggest that A2AR antagonism is able to counteract the deficit in D2R-mediated transmission observed in mutant mice, opening new perspectives for the treatment of this movement disorder.
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http://dx.doi.org/10.1016/j.nbd.2010.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906674PMC
June 2010

Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine.

Brain 2009 Sep 29;132(Pt 9):2336-49. Epub 2009 Jul 29.

Department of Neuroscience, University Tor Vergata, 00133 Rome, Italy.

DYT1 dystonia is a severe form of inherited dystonia, characterized by involuntary twisting movements and abnormal postures. It is linked to a deletion in the dyt1 gene, resulting in a mutated form of the protein torsinA. The penetrance for dystonia is incomplete, but both clinically affected and non-manifesting carriers of the DYT1 mutation exhibit impaired motor learning and evidence of altered motor plasticity. Here, we characterized striatal glutamatergic synaptic plasticity in transgenic mice expressing either the normal human torsinA or its mutant form, in comparison to non-transgenic (NT) control mice. Medium spiny neurons recorded from both NT and normal human torsinA mice exhibited normal long-term depression (LTD), whereas in mutant human torsinA littermates LTD could not be elicited. In addition, although long-term potentiation (LTP) could be induced in all the mice, it was greater in magnitude in mutant human torsinA mice. Low-frequency stimulation (LFS) can revert potentiated synapses to resting levels, a phenomenon termed synaptic depotentiation. LFS induced synaptic depotentiation (SD) both in NT and normal human torsinA mice, but not in mutant human torsinA mice. Since anti-cholinergic drugs are an effective medical therapeutic option for the treatment of human dystonia, we reasoned that an excess in endogenous acetylcholine could underlie the synaptic plasticity impairment. Indeed, both LTD and SD were rescued in mutant human torsinA mice either by lowering endogenous acetylcholine levels or by antagonizing muscarinic M1 receptors. The presence of an enhanced acetylcholine tone was confirmed by the observation that acetylcholinesterase activity was significantly increased in the striatum of mutant human torsinA mice, as compared with both normal human torsinA and NT littermates. Moreover, we found similar alterations of synaptic plasticity in muscarinic M2/M4 receptor knockout mice, in which an increased striatal acetylcholine level has been documented. The loss of LTD and SD on one hand, and the increase in LTP on the other, demonstrate that a 'loss of inhibition' characterizes the impairment of synaptic plasticity in this model of DYT1 dystonia. More importantly, our results indicate that an unbalanced cholinergic transmission plays a pivotal role in these alterations, providing a clue to understand the ability of anticholinergic agents to restore motor deficits in dystonia.
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http://dx.doi.org/10.1093/brain/awp194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766181PMC
September 2009

Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystonia.

Neurobiol Dis 2009 Apr 13;34(1):133-45. Epub 2009 Jan 13.

Department of Neuroscience, University "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.

DYT1 dystonia is caused by a deletion in a glutamic acid residue in the C-terminus of the protein torsinA, whose function is still largely unknown. Alterations in GABAergic signaling have been involved in the pathogenesis of dystonia. We recorded GABA- and glutamate-mediated synaptic currents from a striatal slice preparation obtained from a mouse model of DYT1 dystonia. In medium spiny neurons (MSNs) from mice expressing human mutant torsinA (hMT), we observed a significantly higher frequency, but not amplitude, of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature currents (mIPSCs), whereas glutamate-dependent spontaneous excitatory synaptic currents (sEPSCs) were normal. No alterations were found in mice overexpressing normal human torsinA (hWT). To identify the possible sources of the increased GABAergic tone, we recorded GABAergic Fast-Spiking (FS) interneurons that exert a feed-forward inhibition on MSNs. However, both sEPSC and sIPSC recorded from hMT FS interneurons were comparable to hWT and non-transgenic (NT) mice. In physiological conditions, dopamine (DA) D2 receptor act presynaptically to reduce striatal GABA release. Of note, application of the D2-like receptor agonist quinpirole failed to reduce the frequency of sIPSCs in MSNs from hMT as compared to hWT and NT mice. Likewise, the inhibitory effect of quinpirole was lost on evoked IPSCs both in MSNs and FS interneurons from hMT mice. Our findings demonstrate a disinhibition of striatal GABAergic synaptic activity, that can be at least partially attributed to a D2 DA receptor dysfunction.
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http://dx.doi.org/10.1016/j.nbd.2009.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786200PMC
April 2009

Seletracetam (ucb 44212) inhibits high-voltage-activated Ca2+ currents and intracellular Ca2+ increase in rat cortical neurons in vitro.

Epilepsia 2009 Apr 4;50(4):702-10. Epub 2008 Dec 4.

Department of Neuroscience, University of Rome Tor Vergata, and Fondazione Santa Lucia, IRCCS, Rome, Italy.

Purpose: We analyzed the effects of seletracetam (ucb 44212; SEL), a new antiepileptic drug candidate, in an in vitro model of epileptic activity. The activity of SEL was compared to the effects of levetiracetam (LEV; Keppra), in the same assays.

Methods: Combined electrophysiologic and microfluorometric recordings were performed from layer V pyramidal neurons in rat cortical slices to study the effects of SEL on the paroxysmal depolarization shifts (PDSs), and the simultaneous elevations of intracellular Ca(2+) concentration [Ca(2+)](i). Moreover, the involvement of high-voltage activated Ca(2+) currents (HVACCs) was investigated by means of patch-clamp recordings from acutely dissociated pyramidal neurons.

Results: SEL significantly reduced both the duration of PDSs (IC(50) = 241.0 +/- 21.7 nm) as well as the number of action potentials per PDS (IC(50) = 82.7 +/- 9.7 nm). In addition, SEL largely decreased the [Ca(2+)](i) rise accompanying PDSs (up to 75% of control values, IC(50) = 345.0 +/- 15.0 nm). Furthermore, SEL significantly reduced HVACCs in pyramidal neurons. This effect was mimicked by omega-conotoxin GVIA and, to a lesser extent, by omega-conotoxin MVIIC, blockers of N- and Q-type HVACC, respectively. The combination of these two toxins occluded the action of SEL, suggesting that N-type Ca(2+) channels, and partly Q-type subtypes are preferentially targeted.

Conclusions: These results demonstrate a powerful inhibitory effect of SEL on epileptiform events in vitro. SEL showed a higher potency than LEV. The effective limitation of [Ca(2+)](i) influx might be relevant for its antiepileptic efficacy and, more broadly, for pathologic processes involving neuronal [Ca(2+)](i) overload.
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http://dx.doi.org/10.1111/j.1528-1167.2008.01915.xDOI Listing
April 2009

Loss of muscarinic autoreceptor function impairs long-term depression but not long-term potentiation in the striatum.

J Neurosci 2008 Jun;28(24):6258-63

Fondazione Santa Lucia Instituto di Ricovero e Cura a Carattere Scientifico, Rome 00146, Italy.

Muscarinic autoreceptors regulate cholinergic tone in the striatum. We investigated the functional consequences of genetic deletion of striatal muscarinic autoreceptors by means of electrophysiological recordings from either medium spiny neurons (MSNs) or cholinergic interneurons (ChIs) in slices from single M(4) or double M(2)/M(4) muscarinic acetylcholine receptor (mAChR) knock-out (-/-) mice. In control ChIs, the muscarinic agonist oxotremorine (300 nM) produced a self-inhibitory outward current that was mostly reduced in M(4)(-/-) and abolished in M(2)/M(4)(-/-) mice, suggesting an involvement of both M(2) and M(4) autoreceptors. In MSNs from both M(4)(-/-) and M(2)/M(4)(-/-) mice, muscarine caused a membrane depolarization that was prevented by the M(1) receptor-preferring antagonist pirenzepine (100 nM), suggesting that M(1) receptor function was unaltered. Acetylcholine has been involved in striatal long-term potentiation (LTP) or long-term depression (LTD) induction. Loss of muscarinic autoreceptor function is predicted to affect synaptic plasticity by modifying striatal cholinergic tone. Indeed, high-frequency stimulation of glutamatergic afferents failed to induce LTD in MSNs from both M(4)(-/-) and M(2)/M(4)(-/-) mice, as well as in wild-type mice pretreated with the M(2)/M(4) antagonist AF-DX384 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,1 1-dihydro-6H-pyrido[2,3b][1,4] benzodiazepin-6-one). Interestingly, LTD could be restored by either pirenzepine (100 nM) or hemicholinium-3 (10 microM), a depletor of endogenous ACh. Conversely, LTP induction did not show any difference among the three mouse strains and was prevented by pirenzepine. These results demonstrate that M(2)/M(4) muscarinic autoreceptors regulate ACh release from striatal ChIs. As a consequence, endogenous ACh drives the polarity of bidirectional synaptic plasticity.
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http://dx.doi.org/10.1523/JNEUROSCI.1678-08.2008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849426PMC
June 2008

Functional and ultrastructural analysis of group I mGluR in striatal fast-spiking interneurons.

Eur J Neurosci 2007 Mar;25(5):1319-31

Fondazione Santa Lucia I.R.C.C.S., Department of Neuroscience, Clinica Neurologica, University Tor Vergata, Via Montpellier, 00133 Rome, Italy.

Striatal parvalbumin-containing fast-spiking (FS) interneurons provide a powerful feedforward GABAergic inhibition on spiny projection neurons, through a widespread arborization and electrical coupling. Modulation of FS interneuron activity might therefore strongly affect striatal output. Metabotropic glutamate receptors (mGluRs) exert a modulatory action at various levels in the striatum. We performed electrophysiological recordings from a rat striatal slice preparation to investigate the effects of group I mGluR activation on both the intrinsic and synaptic properties of FS interneurons. Bath-application of the group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine (3,5-DHPG), caused a dose-dependent depolarizing response. Both (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385) and 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), selective mGluR1 antagonists, significantly reduced the amplitude of the membrane depolarization caused by 3,5-DHPG application. Conversely, mGluR5 antagonists, 2-methyl-6-(phenylethylnyl)pyridine hydrochloride (MPEP) and 6-methyl-2-(phenylazo)-3-pyridinol (SIB1757), were unable to affect the response to 3,5-DHPG, suggesting that only mGluR1 contributes to the 3,5-DHPG-mediated excitatory action on FS interneurons. Furthermore, mGluR1 blockade significantly decreased the amplitude of the glutamatergic postsynaptic potentials, whereas the mGluR5 antagonist application produced a small nonsignificant inhibitory effect. Surprisingly, our electron microscopic data demonstrate that the immunoreactivity for both mGluR1a and mGluR5 is expressed extrasynaptically on the plasma membrane of parvalbumin-immunoreactive dendrites of FS interneurons. Together, these results suggest that despite a common pattern of distribution, mGluR1 and mGluR5 exert distinct functions in the modulation of FS interneuron activity.
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http://dx.doi.org/10.1111/j.1460-9568.2007.05383.xDOI Listing
March 2007

Endogenous serotonin excites striatal cholinergic interneurons via the activation of 5-HT 2C, 5-HT6, and 5-HT7 serotonin receptors: implications for extrapyramidal side effects of serotonin reuptake inhibitors.

Neuropsychopharmacology 2007 Aug 3;32(8):1840-54. Epub 2007 Jan 3.

Fondazione Santa Lucia I.R.C.C.S., European Brain Research Institute, Rome, Italy.

The striatum is richly innervated by serotonergic afferents from the raphe nucleus. We explored the effects of this input on striatal cholinergic interneurons from rat brain slices, by means of both conventional intracellular and whole-cell patch-clamp recordings. Bath-applied serotonin (5-HT, 3-300 microM), induced a dose-dependent membrane depolarization and increased the rate of spiking. This effect was mimicked by the 5-HT reuptake blockers citalopram and fluvoxamine. In voltage-clamped neurons, 5-HT induced an inward current, whose reversal potential was close to the K(+) equilibrium potential. Accordingly, the involvement of K(+) channels was confirmed either by increasing extracellular K(+) concentration and by blockade of K(+) channels with barium. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) profiling demonstrated the presence of 5-HT2C, 5-HT6, and 5-HT7 receptor mRNAs in identified cholinergic interneurons. The depolarization/inward current induced by 5-HT was partially mimicked by the 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine and antagonized by both ketanserin and the selective 5-HT2C antagonist RS102221, whereas the selective 5-HT3 and 5-HT4 receptor antagonists tropisetron and RS23597-190 had no effect. The depolarizing response to 5-HT was also reduced by the selective 5-HT6 and 5-HT7 receptor antagonists SB258585 and SB269970, respectively, and mimicked by the 5-HT7 agonist, 5-CT. Accordingly, activation of either 5-HT6 or 5-HT7 receptor induced an inward current. The 5-HT response was attenuated by U73122, blocker of phospholipase C, and by SQ22,536, an inhibitor of adenylyl cyclase. These results suggest that 5-HT released by serotonergic fibers originating in the raphe nuclei has a potent excitatory effect on striatal cholinergic interneurons.
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http://dx.doi.org/10.1038/sj.npp.1301294DOI Listing
August 2007