Laboratory of Neurophysiology and Plasticity

Santa Lucia di Serino, Italy

Laboratory of Neurophysiology and Plasticity

Santa Lucia di Serino, Italy
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Martella G.,University of Rome Tor Vergata | Madeo G.,University of Rome Tor Vergata | Schirinzi T.,University of Rome Tor Vergata | Tassone A.,Laboratory of Neurophysiology and Plasticity | And 7 more authors.
Neuroscience | Year: 2011

In the present work we analyzed the profile of high voltage-activated (HVA) calcium (Ca 2+) currents in freshly isolated striatal medium spiny neurons (MSNs) from rodent models of both idiopathic and familial forms of Parkinson's disease (PD). MSNs were recorded from reserpine-treated and 6-hydroxydopamine (6-OHDA)-lesioned rats, and from DJ-1 and PINK1 (PTEN induced kinase 1) knockout ( -/-) mice. Our analysis showed no significant changes in total HVA Ca 2+ current. However, we recorded a net increase in the L-type fraction of HVA Ca 2+ current in dopamine-depleted rats, and of both N- and P-type components in DJ-1 -/- mice, whereas no significant change in Ca 2+ current profile was observed in PINK1 -/- mice. Dopamine modulates HVA Ca 2+ channels in MSNs, thus we also analyzed the effect of D1 and D2 receptor activation. The effect of the D1 receptor agonist SKF 83822 on Ca 2+ current was not significantly different among MSNs from control animals or PD models. However, in both dopamine-depleted rats and DJ-1 -/- mice the D2 receptor agonist quinpirole inhibited a greater fraction of HVA Ca 2+ current than in the respective controls. Conversely, in MSNs from PINK1 -/- mice we did not observe alterations in the effect of D2 receptor activation. Additionally, in both reserpine-treated and 6-OHDA-lesioned rats, the effect of quinpirole was occluded by the selective L-type Ca 2+ channel blocker nifedipine, while in DJ-1 -/- mice it was mostly occluded by ω-conotoxin GVIA, blocker of N-type channels. These results demonstrate that both dopamine depletion and DJ-1 deletion induce a rearrangement in the HVA Ca 2+ channel profile, specifically involving those channels that are selectively modulated by D2 receptors. © 2011 IBRO.


Martella G.,University of Rome Tor Vergata | Martella G.,Laboratory of Neurophysiology and Plasticity | Madeo G.,University of Rome Tor Vergata | Madeo G.,Laboratory of Neurophysiology and Plasticity | And 14 more authors.
Neurobiology of Disease | Year: 2016

Heterozygous mutations in the PINK1 gene are considered a susceptibility factor to develop early-onset Parkinson's disease (PD), as supported by dopamine hypometabolism in asymptomatic mutation carriers and subtle alterations of dopamine-dependent striatal synaptic plasticity in heterozygous PINK1 knockout (PINK1+/-) mice. The aim of the present study was to investigate whether exposure to low-dose rotenone of heterozygous PINK1+/- mice, compared to their wild-type PINK1+/+ littermates, could impact on dopamine-dependent striatal synaptic plasticity, in the absence of apparent structural alterations.Mice were exposed to a range of concentrations of rotenone (0.01-1 mg/kg). Chronic treatment with concentrations of rotenone up to 0.8 mg/kg did not cause manifest neuronal loss or changes in ATP levels both in the striatum or substantia nigra of PINK1+/- and PINK1+/+ mice. Moreover, rotenone (up to 0.8 mg/kg) treatment did not induce mislocalization of the mitochondrial membrane protein Tom20 and release of cytochrome c in PINK1+/- striata. Accordingly, basic electrophysiological properties of nigral dopaminergic and striatal medium spiny neurons (MSNs) were normal. Despite the lack of gross alterations in neuronal viability in chronically-treated PINK1+/-, a complete loss of both long-term depression (LTD) and long-term potentiation (LTP) was recorded in MSNs from PINK1+/- mice treated with a low rotenone (0.1 mg/kg) concentration. Even lower concentrations (0.01 mg/kg) blocked LTP induction in heterozygous PINK1+/- MSNs compared to PINK1+/+ mice. Of interest, chronic pretreatment with the antioxidants alpha-tocopherol and Trolox, a water-soluble analog of vitamin E and powerful antioxidant, rescued synaptic plasticity impairment, confirming that, at the doses we utilized, rotenone did not induce irreversible alterations.In this model, chronic exposure to low-doses of rotenone was not sufficient to alter mitochondrial integrity and ATP production, but profoundly impaired the expression of long-term plasticity at corticostriatal synapses in PINK1 heterozygous knockout mice, suggesting that disruption of synaptic plasticity may represent an early feature of a pre-manifesting state of the disease, and a potential tool to test novel neuroprotective agents. © 2016 Elsevier Inc.


Ponterio G.,University of Rome Tor Vergata | Ponterio G.,Laboratory of Neurophysiology and Plasticity | Tassone A.,Laboratory of Neurophysiology and Plasticity | Sciamanna G.,Laboratory of Neurophysiology and Plasticity | And 5 more authors.
Neuropharmacology | Year: 2013

Cholinergic interneurons (ChIs) of dorsal striatum play a key role in motor control and in behavioural learning. Neuropeptides regulate cholinergic transmission and mu opioid receptor (MOR) activation modulates striatal acetylcholine release. However, the mechanisms underlying this effect are yet uncharacterized. Here, we examined the electrophysiological responses of ChIs to the selective MOR agonist, DAMGO {[D-Ala2-MePhe4-Gly(ol)5] enkephalin}. We observed a robust, dose-dependent inhibition of spontaneous firing activity (0.06-3 μM) which was reversible upon drug washout and blocked by the selective antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) (1 μM). Voltage-clamp analysis of the reversal potential of the DAMGO effect did not provide univocal results, indicating the involvement of multiple membrane conductances. The MOR-dependent effect persisted in the presence of GABAA and ionotropic glutamate receptor antagonists, ruling out an indirect effect. Additionally, it depended upon G-protein activation, as it was prevented by intrapipette GDP-β-S. Because D2 dopamine receptors (D2R) and MOR share a common post-receptor signalling pathway, occlusion experiments were performed with maximal doses of both D2R and MOR agonists. The D2R agonist quinpirole decreased spike discharge, which was further reduced by adding DAMGO. Then, D2R or MOR antagonists were used to challenge the response to the respective agonists, DAMGO or quinpirole. No cross-effect was observed, suggesting that the two receptors act independently. Our findings demonstrate a postsynaptic inhibitory modulation by MOR on ChIs excitability. Such opioidergic regulation of cholinergic transmission might contribute to shape information processing in basal ganglia circuits, and represent a potential target for pharmacological intervention. © 2013 Published by Elsevier Ltd.


Eskow Jaunarajs K.L.,University of Alabama at Birmingham | Bonsi P.,Laboratory of Neurophysiology and Plasticity | Chesselet M.F.,University of California at Los Angeles | Standaert D.G.,University of Alabama at Birmingham | And 2 more authors.
Progress in Neurobiology | Year: 2015

Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestation of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia. © 2015 Elsevier Ltd.


Tassone A.,Laboratory of Neurophysiology and Plasticity | Tassone A.,University of Rome Tor Vergata | Madeo G.,University of Rome Tor Vergata | Schirinzi T.,University of Rome Tor Vergata | And 8 more authors.
Neuropharmacology | Year: 2011

We investigated the effect of 5-HT6 receptor subtype activation on glutamatergic transmission by means of whole-cell patch-clamp electrophysiological recordings from medium spiny neurons of the striatum and layer V pyramidal neurons of the prefrontal cortex. To this aim, we took advantage of a novel ligand, ST1936, showing nM affinity and agonist activity at the 5-HT6 receptor subtype. Our data show that 5-HT6 receptor activation by ST1936 reduces the frequency of spontaneous excitatory postsynaptic currents, with an IC50 of 1.3 μM. Moreover, 5-HT6 receptor activation also reduced the amplitude of spontaneous excitatory postsynaptic currents recorded from medium spiny neurons, suggesting a mechanism of action involving postsynaptic 5-HT6 receptors,as further confirmed by the paired-pulse analysis on evoked excitatory postsynaptic currents and by recordings of miniature glutamatergic events. The inhibitory effect of ST1936 on glutamatergic transmission was prevented by the selective 5-HT6 receptor antagonist SB258585 and mimicked by a different agonist, WAY-181187. Conversely, in the cortex ST1936 reduced the frequency, but not the amplitude, of spontaneous excitatory postsynaptic currents suggesting a presynaptic or indirect effect of the 5-HT6 receptor. © 2011 Published by Elsevier Ltd.


Sciamanna G.,University of Rome Tor Vergata | Sciamanna G.,Laboratory of Neurophysiology and Plasticity | Tassone A.,University of Rome Tor Vergata | Tassone A.,Laboratory of Neurophysiology and Plasticity | And 11 more authors.
PLoS ONE | Year: 2011

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. © 2011 Sciamanna et al.


PubMed | Laboratory of Neurophysiology and Plasticity, University of California at Los Angeles, University of Alabama at Birmingham and University of Rome Tor Vergata
Type: | Journal: Progress in neurobiology | Year: 2015

Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestation of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia.


Sciamanna G.,Laboratory of Neurophysiology and Plasticity | Wilson C.J.,University of Texas at San Antonio
Journal of Neurophysiology | Year: 2011

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. © 2011 the American Physiological Society.


Bonsi P.,Laboratory of Neurophysiology and Plasticity | Cuomo D.,University of Rome Tor Vergata | Martella G.,University of Rome Tor Vergata | Madeo G.,University of Rome Tor Vergata | And 5 more authors.
Frontiers in Neuroanatomy | Year: 2011

Work over the past two decades revealed a previously unexpected role for striatal cholinergic interneurons in the context of basal ganglia function. The recognition that these interneurons are essential in synaptic plasticity and motor learning represents a significant step ahead in deciphering how the striatum processes cortical inputs, and why pathological circumstances cause motor dysfunction. Loss of the reciprocal modulation between dopaminergic inputs and the intrinsic cholinergic innervation within the striatum appears to be the trigger for pathophysiological changes occurring in basal ganglia disorders. Accordingly, there is now compelling evidence showing profound changes in cholinergic markers in these disorders, in particular Parkinson's disease and dystonia. Based on converging experimental and clinical evidence, we provide an overview of the role of striatal cholinergic transmission in physiological and pathological conditions, in the context of the pathogenesis of movement disorders. © 2011 Bonsi, Cuomo, Martella, Madeo, Schirinzi, Puglisi, Ponterio and Pisani.


Vanni V.,University of Rome Tor Vergata | Vanni V.,Laboratory of Neurophysiology and Plasticity | Puglisi F.,Laboratory of Neurophysiology and Plasticity | Bonsi P.,Laboratory of Neurophysiology and Plasticity | And 8 more authors.
Experimental Neurology | Year: 2015

Early-onset torsion dystonia (DYT1) is an autosomal-dominant movement disorder characterized by sustained muscle contractions and abnormal posturing. It is caused by a three base-pair deletion (δGAG) in the gene encoding the AAA+ protein torsinA, which gives rise to a loss of function mutation responsible of neuronal functional abnormalities. Symptoms typically appear during childhood, suggesting the presence of an early critical period of sensorimotor circuit susceptibility to torsinA dysfunction. Here, we identified in two different DYT1 mouse strains, heterozygous torsinA knockout mice (Tor1a+/-) and human δGAG mutant torsinA transgenic mice (hMT), the anatomical abnormalities in the cerebellum, during a critical age for synaptogenesis (postnatal day 14, P14). By means of immunofluorescence, confocal analysis and western blot quantification, we observed a reduced inhibitory input on Purkinje cells (PCs) as well as an unbalanced excitatory innervation; a significant reduction of the parallel fiber (PF) synaptic terminals and an increase of the climbing fiber (CF) inputs. Finally, in support of the in vivo results, we also provide evidence of an impaired PF synaptogenesis in a co-culture system. Of note, these alterations were rescued and in part over-compensated in the adult age in both mouse strains, suggesting that torsinA dysfunction can induce an altered maturation of cerebellar synaptic contacts. Altogether these results indicate that a loss of function of torsinA during cerebellar synaptogenesis induces important developmental alterations, that might contribute to the age-dependent susceptibility to develop dystonia in mutation carriers. © 2015 Elsevier Inc.

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