Cortico-Subcortical Dynamics in Parkinson¿s Disease, 2008
Recent advances in our knowledge of striatal function revealed a previously unexpected role for s... more Recent advances in our knowledge of striatal function revealed a previously unexpected role for striatal cholinergic interneurons. The recognition that interneurons are essential in synaptic plasticity and motor learning represents a significant progress 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
Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for... more 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.
Current knowledge of the pathogenesis of basal ganglia disorders, such as Huntington&... more Current knowledge of the pathogenesis of basal ganglia disorders, such as Huntington's disease (HD) and Parkinson's disease (PD) appoints a central role to a dysfunction in mitochondrial metabolism. The development of animal models, based upon the use of mitochondrial toxins has been successfully introduced to reproduce human disease, leading to important acquisitions. Most notably, experimental evidence supports the existence, within basal ganglia, of a peculiar regional vulnerability to distinct mitochondrial toxins. MPTP and rotenone, both selective inhibitors of mitochondrial complex I have been extensively used to mimic PD. Accordingly, in human PD, a specific dysfunction of complex I activity was found in vulnerable dopaminergic neurons of the substantia nigra. Conversely, in HD a selective impairment of mitochondrial succinate dehydrogenase, key enzyme in complex II activity was found in medium spiny neurons of the caudate-putamen. The relevance of such finding is further demonstrated by the evidence that toxins able to primarily target mitochondrial complex II, such as malonic acid and 3-nitropropionic acid (3-NP), strikingly reproduce the main phenotypic and pathological features of HD.Despite the advances obtained from these experimental models, a deeper understanding of the molecular and cellular mechanisms underlying such neuronal vulnerability is lacking.The present review provides a brief survey of currently utilized animal models of mitochondrial intoxication, in attempt to address the cellular mechanisms triggered by energy metabolism failure and to identify potential therapeutic targets.
Pathophysiology, Pharmacology, and Biochemistry of Dyskinesia, 2011
Dystonia is a disabling movement disorder characterized by involuntary, sustained muscle contract... more 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.
In the recent past, the pathogenesis of Parkinson's disease (PD) has evolved from a neuro... more In the recent past, the pathogenesis of Parkinson's disease (PD) has evolved from a neurodegenerative disorder considered entirely sporadic to a disease with an unequivocal genetic component. Indeed, different inherited forms of PD have been discovered and characterized, although the functional roles of the gene products identified are still under intense investigation. To gain a better understanding of the cellular and molecular pathogenic mechanisms of hereditary forms of PD, different animal models have been generated. Although most of the rodent models display neither obvious behavioral impairment nor evidence for neurodegeneration, remarkable abnormalities of dopamine-mediated neurotransmission and corticostriatal synaptic plasticity have been described, indicative of a fundamental distortion of network function within the basal ganglia. The picture emerging from a critical review of recent data on monogenic parkinsonisms suggests that mutations in PD genes might cause developmental rearrangements in the corticobasal ganglia circuitry, compensating the dopaminergic dysfunction observed both in mice and humans, in order to maintain proper motor function.
Previous work has shown that enkephalins target N-type calcium (Ca2+) channels in striatal and gl... more Previous work has shown that enkephalins target N-type calcium (Ca2+) channels in striatal and globus pallidus (GP) neurons, principally through activation of mu-like receptors. Here, we examined the effects of selective mu, delta, and kappa agonists on Ca2+ currents in striatal and GP neurons isolated from either control or reserpine-treated rats. In cells from control rats DAMGO and dynorphin (DYN) inhibited high-voltage-activated (HVA) Ca2+ currents preferentially in "medium-to-small" GP cells (likely to correspond to parvalbumin-negative cells). The kappa response was elicited by several agonists (DYN 17, DYN 13, BRL, U50-488-H), U50-488-H being the most effective (>30% maximal inhibition). U50-488-H affected both omega-CgTxGVIA-sensitive and nimodipine-sensitive Ca2+ conductances. The kappa-mediated effect (but not the mu response) was slow and blocked by chelerythrine, supporting the involvement of protein kinase C. In neurons from reserpinized rats we observed modest changes in the mu-inhibited fraction in small GP cells and a dramatic reduction of the kappa-sensitive fraction in principal striatal cells. These data imply that aminergic depletion alters opiate transmission differentially in the indirect and direct pathways. The suppression of the kappa response only in striatum reinforces the notion of an imbalance of endogenous opiates as relevant in extrapyramidal motor dysfunctions.
Proceedings. 25th Annual 1991 IEEE International Carnahan Conference on Security Technology, 1991
ABSTRACT A real-time security system (RETISS) for threat detection is described, pointing out sec... more ABSTRACT A real-time security system (RETISS) for threat detection is described, pointing out security violations in the target system under control. RETISS is based on the hypothesis that a correlation exists between anomalous user behavior and threats. Security rules have been enforced to express this correlation and to detect and evaluate the probability of a given threat, based on the level of danger of the occurrences of the anomalies symptomatic for the threat. Levels of danger of all the anomalies are then fuzzy combined to express the probability of the threat. RETISS is independent of any particular system and application environment. Moreover, RETISS runs on a machine different from that of the target system in order to be protected against attacks from users of the target system
In the present work we analyzed the profile of high voltage-activated (HVA) calcium (Ca2+) curren... more In the present work we analyzed the profile of high voltage-activated (HVA) calcium (Ca2+) 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 Ca2+ current. However, we recorded a net increase in the L-type fraction of HVA Ca2+ current in dopamine-depleted rats, and of both N- and P-type components in DJ-1-/- mice, whereas no significant change in Ca2+ current profile was observed in PINK1-/- mice. Dopamine modulates HVA Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ channel profile, specifically involving those channels that are selectively modulated by D2 receptors.
Cortico-Subcortical Dynamics in Parkinson¿s Disease, 2008
Recent advances in our knowledge of striatal function revealed a previously unexpected role for s... more Recent advances in our knowledge of striatal function revealed a previously unexpected role for striatal cholinergic interneurons. The recognition that interneurons are essential in synaptic plasticity and motor learning represents a significant progress 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
Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for... more 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.
Current knowledge of the pathogenesis of basal ganglia disorders, such as Huntington&... more Current knowledge of the pathogenesis of basal ganglia disorders, such as Huntington's disease (HD) and Parkinson's disease (PD) appoints a central role to a dysfunction in mitochondrial metabolism. The development of animal models, based upon the use of mitochondrial toxins has been successfully introduced to reproduce human disease, leading to important acquisitions. Most notably, experimental evidence supports the existence, within basal ganglia, of a peculiar regional vulnerability to distinct mitochondrial toxins. MPTP and rotenone, both selective inhibitors of mitochondrial complex I have been extensively used to mimic PD. Accordingly, in human PD, a specific dysfunction of complex I activity was found in vulnerable dopaminergic neurons of the substantia nigra. Conversely, in HD a selective impairment of mitochondrial succinate dehydrogenase, key enzyme in complex II activity was found in medium spiny neurons of the caudate-putamen. The relevance of such finding is further demonstrated by the evidence that toxins able to primarily target mitochondrial complex II, such as malonic acid and 3-nitropropionic acid (3-NP), strikingly reproduce the main phenotypic and pathological features of HD.Despite the advances obtained from these experimental models, a deeper understanding of the molecular and cellular mechanisms underlying such neuronal vulnerability is lacking.The present review provides a brief survey of currently utilized animal models of mitochondrial intoxication, in attempt to address the cellular mechanisms triggered by energy metabolism failure and to identify potential therapeutic targets.
Pathophysiology, Pharmacology, and Biochemistry of Dyskinesia, 2011
Dystonia is a disabling movement disorder characterized by involuntary, sustained muscle contract... more 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.
In the recent past, the pathogenesis of Parkinson's disease (PD) has evolved from a neuro... more In the recent past, the pathogenesis of Parkinson's disease (PD) has evolved from a neurodegenerative disorder considered entirely sporadic to a disease with an unequivocal genetic component. Indeed, different inherited forms of PD have been discovered and characterized, although the functional roles of the gene products identified are still under intense investigation. To gain a better understanding of the cellular and molecular pathogenic mechanisms of hereditary forms of PD, different animal models have been generated. Although most of the rodent models display neither obvious behavioral impairment nor evidence for neurodegeneration, remarkable abnormalities of dopamine-mediated neurotransmission and corticostriatal synaptic plasticity have been described, indicative of a fundamental distortion of network function within the basal ganglia. The picture emerging from a critical review of recent data on monogenic parkinsonisms suggests that mutations in PD genes might cause developmental rearrangements in the corticobasal ganglia circuitry, compensating the dopaminergic dysfunction observed both in mice and humans, in order to maintain proper motor function.
Previous work has shown that enkephalins target N-type calcium (Ca2+) channels in striatal and gl... more Previous work has shown that enkephalins target N-type calcium (Ca2+) channels in striatal and globus pallidus (GP) neurons, principally through activation of mu-like receptors. Here, we examined the effects of selective mu, delta, and kappa agonists on Ca2+ currents in striatal and GP neurons isolated from either control or reserpine-treated rats. In cells from control rats DAMGO and dynorphin (DYN) inhibited high-voltage-activated (HVA) Ca2+ currents preferentially in "medium-to-small" GP cells (likely to correspond to parvalbumin-negative cells). The kappa response was elicited by several agonists (DYN 17, DYN 13, BRL, U50-488-H), U50-488-H being the most effective (>30% maximal inhibition). U50-488-H affected both omega-CgTxGVIA-sensitive and nimodipine-sensitive Ca2+ conductances. The kappa-mediated effect (but not the mu response) was slow and blocked by chelerythrine, supporting the involvement of protein kinase C. In neurons from reserpinized rats we observed modest changes in the mu-inhibited fraction in small GP cells and a dramatic reduction of the kappa-sensitive fraction in principal striatal cells. These data imply that aminergic depletion alters opiate transmission differentially in the indirect and direct pathways. The suppression of the kappa response only in striatum reinforces the notion of an imbalance of endogenous opiates as relevant in extrapyramidal motor dysfunctions.
Proceedings. 25th Annual 1991 IEEE International Carnahan Conference on Security Technology, 1991
ABSTRACT A real-time security system (RETISS) for threat detection is described, pointing out sec... more ABSTRACT A real-time security system (RETISS) for threat detection is described, pointing out security violations in the target system under control. RETISS is based on the hypothesis that a correlation exists between anomalous user behavior and threats. Security rules have been enforced to express this correlation and to detect and evaluate the probability of a given threat, based on the level of danger of the occurrences of the anomalies symptomatic for the threat. Levels of danger of all the anomalies are then fuzzy combined to express the probability of the threat. RETISS is independent of any particular system and application environment. Moreover, RETISS runs on a machine different from that of the target system in order to be protected against attacks from users of the target system
In the present work we analyzed the profile of high voltage-activated (HVA) calcium (Ca2+) curren... more In the present work we analyzed the profile of high voltage-activated (HVA) calcium (Ca2+) 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 Ca2+ current. However, we recorded a net increase in the L-type fraction of HVA Ca2+ current in dopamine-depleted rats, and of both N- and P-type components in DJ-1-/- mice, whereas no significant change in Ca2+ current profile was observed in PINK1-/- mice. Dopamine modulates HVA Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ channel profile, specifically involving those channels that are selectively modulated by D2 receptors.
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