Biomedical subjects

Paolo Calabresi

Publications and source records attributed to Paolo Calabresi.

At least 37 records · Page 2Linked to original sources

PubMed2005

Pathological synaptic plasticity in the striatum: implications for Parkinson's disease.

Repetitive stimulation of the corticostriatal pathway can cause either a long-lasting increase, or an enduring decrease in synaptic strength, respectively referred to as long-term potentiation (LTP), and long-term depression (LTD), both requiring a complex sequence of biochemical events. Once established, LTP can be reversed to control levels by a low-frequency stimulation (LFS) protocol, an active phenomenon defined "synaptic depotentiation", required to erase redundant information. In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), striatal synaptic plasticity has been shown to be impaired, though chronic treatment with l-dopa was able to restore it. Interestingly, a consistent number of l-dopa-treated animals developed involuntary movements, resembling human dyskinesias. Strikingly, electrophysiological recordings from the dyskinetic group of rats demonstrated a selective impairment of synaptic depotentiation. This survey will provide an overview of plastic changes occurring at striatal synapses. The potential relevance of these findings in the control of motor function and in the pathogenesis both of Parkinson's disease and l-dopa-induced motor complications will be discussed.

Animals↗

PubMed2005

Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1.

The manifestations of Parkinson's disease are caused by reduced dopaminergic innervation of the striatum. Loss-of-function mutations in the DJ-1 gene cause early-onset familial parkinsonism. To investigate a possible role for DJ-1 in the dopaminergic system, we generated a mouse model bearing a germline disruption of DJ-1. Although DJ-1(-/-) mice had normal numbers of dopaminergic neurons in the substantia nigra, evoked dopamine overflow in the striatum was markedly reduced, primarily as a result of increased reuptake. Nigral neurons lacking DJ-1 were less sensitive to the inhibitory effects of D2 autoreceptor stimulation. Corticostriatal long-term potentiation was normal in medium spiny neurons of DJ-1(-/-) mice, but long-term depression (LTD) was absent. The LTD deficit was reversed by treatment with D2 but not D1 receptor agonists. Furthermore, DJ-1(-/-) mice displayed hypoactivity in the open field. Collectively, our findings suggest an essential role for DJ-1 in dopaminergic physiology and D2 receptor-mediated functions.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2005

Striatal synaptic plasticity: implications for motor learning and Parkinson's disease.

Changing the strength of synaptic connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. Plastic changes appear to follow a regional specialization and underlie the specific type of memory mediated by the brain area in which plasticity occurs. Thus, long-term changes occurring at excitatory corticostriatal synapses should be critically involved in motor learning. Indeed, repetitive stimulation of the corticostriatal pathway can cause either a long-lasting increase or an enduring decrease in synaptic strength, respectively referred to as long-term potentiation (LTP), and long-term depression, both requiring a complex sequence of biochemical events. Once established, LTP can be reversed to control levels by a low-frequency stimulation protocol, an active phenomenon defined "synaptic depotentiation," required to erase redundant information. In the 6-hydroxydopamine rat model of Parkinson's disease (PD), striatal synaptic plasticity has been shown to be impaired, although chronic treatment with levodopa was able to restore it. Of interest, a consistent number of L-dopa-treated animals developed involuntary movements, resembling human dyskinesias. Strikingly, electrophysiological recordings from the dyskinetic group of rats demonstrated a selective impairment of synaptic depotentiation. This survey will provide an overview of plastic changes occurring at striatal synapses. The potential relevance of these findings in the control of motor function and in the pathogenesis both of PD and L-dopa-induced motor complications will be discussed.

Animals↗

PubMed2005

Medication-overuse headache: pathophysiological insights.

Medication overuse headache (MOH) is a clinically important entity and it is now well documented that the regular use of acute symptomatic medication by people with migraine or tensiontype headache increases the risk of aggravation of the primary headache. MOH is one of the most common causes of chronic migraine-like syndrome. Because of easy availability and low expense, the greatest problem appears to be associated with barbiturate-containing combination analgesics and over-the-counter caffeine-containing combination analgesics. Even though triptan overuse headache is not encountered with great frequency, all triptans should be considered potential inducers of MOH. There are several different theories regarding the aetiology of MOH, including: (i) central sensitisation from repetitive activation of nociceptive pathways; (ii) a direct effect of the medication on the capacity of the brain to inhibit pain; (iii) a decrease in blood serotonin due to repetitive medication administration with alteration of serotonin receptors; (iv) cellular adaptation in the brain; and (v) changes in the periaqueductal grey matter. The principal approach to management of MOH is built around cessation of overused medication. Without discontinuation of the offending medication, improvement is almost impossible to attain. Thus, the best management advice is to raise awareness and strive for prevention. In this article, we analyse also the possible mechanisms that underlie sensitisation in MOH by comparing these mechanisms with those reported for other forms of drug addiction.

Analgesics↗

PubMed2005

Application of ICHD 2nd edition criteria for primary headaches with the aid of a computerised, structured medical record for the specialist.

We tested the computerised, structured medical record by entering and analysing the consecutive clinical sheets of primary headaches in the episodic forms (200) and chronic headache (200) and the corresponding output diagnoses of patients attending our Headache Centre. A diagnosis of one of the primary headache forms was obtained in 67.9% of cases. A certain diagnosis of primary headache plus that of a probable form was obtained in 24.4% of cases (12.7% represented by chronic migraine (CM) or chronic tension-type headache (CTTH)+probable medication overuse headache). Only probable forms were diagnosed in the remaining 7.3% (as single probable diagnosis in 5.8% of cases or multiple diagnoses of probable forms in the remaining ones). The percentage of certain diagnoses mainly in the chronic headache group (28.4%), and to a lesser extent tension-type headache (6.5%), were obtained in 34.9% of cases. A certain diagnosis of one chronic form plus that of a probable form was obtained in 50.8% of cases (26.9% represented by probable medication-overuse headache). Only probable forms were diagnosed in 13.46% (as single probable diagnosis in 8.73% of cases or multiple diagnoses of probable forms in the remaining ones). In the other cases, the ICHD-II classification does not allow the diagnoses of CM, CTTH or probable forms and medication overuse headache because the mandatory criteria for the diagnoses are too stringent and do not reflect modifications of the headache pattern in relation to its chronicity. These preliminary results underscore the usefulness of a computerised device based on the ICHD 2nd edition for diagnostic purposes in tertiary centres dedicated to headaches in clinical practice as well as its relevance for research. This computerised device may help to validate the new diagnostic criteria and to answer some emerging questions from the application of the new classification version, the relevance of which should be verified in clinical practice.

Diagnosis, Computer-Assisted↗

PubMed2005

Medication-overuse headache: similarities with drug addiction.

Medication-overuse headache (MOH) is a clinically important entity and it is now well documented that the regular use of acute symptomatic medication by people with migraine or tension-type headache increases the risk of aggravation of the primary headache. MOH is one the most common causes of chronic migraine-like syndrome. In this article, we analyse the possible mechanisms that underlie sensitization in MOH by comparing these mechanisms with those reported for other forms of drug addiction. Moreover, the evidence for cognitive impulsivity in drug overuse in headache and in other forms of addiction associated with dysfunction of the frontostriatal system will be discussed. An integrative hypothesis for compulsive reward-seeking in MOH will be presented.

Chronic Disease↗

PubMed2005

Inhibition of persistent sodium current fraction and voltage-gated L-type calcium current by propofol in cortical neurons: implications for its antiepileptic activity.

PURPOSE: Although it is widely used in clinical practice, the mechanisms of action of 2,6-di-isopropylphenol (propofol) are not completely understood. We examined the electrophysiologic effects of propofol on an in vitro model of epileptic activity obtained from a slice preparation. METHODS: The effects of propofol were tested both on membrane properties and on epileptiform events consisting of long-lasting, paroxysmal depolarization shifts (PDSs) induced by reducing the magnesium concentration from the solution and by adding bicuculline and 4-aminopyridine. These results were integrated with a patch-clamp analysis of Na(+) and high-voltage activated (HVA) calcium (Ca(2+)) currents from isolated cortical neurons. RESULTS: In bicuculline, to avoid any interference by gamma-aminobutyric acid (GABA)-A receptors, propofol (3-100 microM) did not cause significant changes in the current-evoked, sodium (Na(+))-dependent action-potential discharge. However, propofol reduced both the duration and the number of spikes of PDSs recorded from cortical neurons. Interestingly, relatively low concentrations of propofol [half-maximal inhibitory concentration (IC(50)), 3.9 microM) consistently inhibited the "persistent" fraction of Na(+) currents, whereas even high doses (< or =300 microM) had negligible effects on the "fast" component of Na(+) currents. HVA Ca(2+) currents were significantly reduced by propofol, and the pharmacologic analysis of this effect showed that propofol selectively reduced L-type HVA Ca(2+) currents, without affecting N or P/Q-type channels. CONCLUSIONS: These results suggest that propofol modulates neuronal excitability by selectively suppressing persistent Na(+) currents and L-type HVA Ca(2+) conductances in cortical neurons. These effects might cooperate with the opening of GABA-A-gated chloride channels, to achieve depression of cortical activity during both anesthesia and status epilepticus.

Action Potentials↗

PubMed2005

Removing pathogenic memories: a neurobiology of psychotherapy.

Experimental research examining the neural bases of nondeclarative memory has offered intriguing insight into how functional and dysfunctional implicit learning affects the brain. Long-term modifications of synaptic transmission, in particular, are currently considered the most plausible mechanism underlying memory trace encoding and compulsions, addiction, anxiety, and phobias. Therefore, an effective psychotherapy must be directed to erase maladaptive implicit memories and aberrant synaptic plasticity. This article describes the neurobiological bases of pathogenic memory disruption to provide some insight into how psychotherapy works. At least two mechanisms of unwanted memory erasing appear to be implicated in the effects of psychotherapy: inhibition of memory consolidation/reconsolidation and extinction. Behavioral evidence demonstrated that these two ways to forget are profoundly distinct in nature, and it is increasingly clear that their cellular, synaptic, and molecular underpinnings are different. Accordingly, the blockade of consolidation/reconsolidation erases memories by reversing the plasticity associated with memory maintenance, whereas extinction is a totally new form of plasticity that, similar to the plasticity underlying the old memory, requires protein synthesis-dependent synaptic remodeling.

Humans↗

PubMed2004

Coordinate high-frequency pattern of stimulation and calcium levels control the induction of LTP in striatal cholinergic interneurons.

Current evidence appoints a central role to cholinergic interneurons in modulating striatal function. Recently, a long-term potentiation (LTP) of synaptic transmission has been reported to occur in these neurons. The relationship between the pattern of cortico/thalamostriatal fibers stimulation, the consequent changes in the intracellular calcium concentration ([Ca2+]i), and the induction of synaptic plasticity was investigated in striatal cholinergic interneurons from a rat corticostriatal slice preparation by means of combined electrophysiological intracellular recordings and microfluorometric techniques. Different protocols of stimulation were considered, varying both the frequency and the duration of the train of stimuli. High-frequency stimulation (HFS) (three trains at 100 Hz for 3 sec, 20-sec interval) induced a rise in [Ca2+]i, exceeding by fivefold the resting level, and caused a LTP of synaptic transmission. Tetanic stimulation delivered at lower frequencies (5-30 Hz) failed to induce long-term changes of synaptic efficacy. The observed elevation in [Ca2+]i during HFS was primarily mediated by L-type high-voltage activated (HVA)-Ca2+ channels, as it was fully prevented by nifedipine. Conversely, blockade of NMDA and AMPA glutamate receptor did not affect either LTP or the magnitude of the [Ca2+]i rise. Interestingly, the pharmacological analysis of the post-tetanic depolarizing postsynaptic potential (DPSP) revealed that LTP was attributable, to a large extent, to the potentiation of the GABA(A)-mediated component. In conclusion, the expression of LTP in striatal cholinergic interneurons is a selective response to a precise stimulation pattern of induction requiring a critical rise in [Ca2+]i.

Animals↗

PubMed2004

Chronic haloperidol promotes corticostriatal long-term potentiation by targeting dopamine D2L receptors.

Reduced glutamate-mediated synaptic transmission has been implicated in the pathophysiology of schizophrenia. Because antipsychotic agents might exert their beneficial effects against schizophrenic symptoms by strengthening excitatory transmission in critical dopaminoceptive brain areas, in the present study we have studied the effects of acute and chronic haloperidol treatment on striatal synaptic plasticity. Repetitive stimulation of corticostriatal terminals in slices induced either long-term depression or long-term potentiation (LTP) of excitatory transmission in control rats, whereas it invariably induced NMDA receptor-dependent LTP in animals treated chronically with haloperidol. Haloperidol effects were mimicked and occluded in mice lacking both D2L and D2S isoforms of dopamine D2 receptors (D2R-/-), in mice lacking D2L receptors and expressing normal levels of D2S receptors (D2R-/-;D2L-/-), and in mice lacking D2L receptors and overexpressing D2S receptors (D2L-/-). These data indicate that the blockade of D2L receptors was responsible for the LTP-favoring action of haloperidol in the striatum. In contrast, overexpression of D2S receptors uncovered a facilitatory role of this receptor isoform in LTP formation because LTP recorded from D2L-/- mice, but not those recorded from wild-type, D2R-/-, and D2R-/-;D2L-/- mice, was insensitive to the pharmacological blockade of D1 receptors. The identification of the cellular, molecular, and receptor mechanisms involved in the action of haloperidol in the brain is essential to understand how antipsychotic agents exert their beneficial and side effects.

Animals↗

PubMed2004

Engagement of rat striatal neurons by cortical epileptiform activity investigated with paired recordings.

The striatum is thought to play an important role in the spreading of epilepsy from cortical areas to deeper brain structures, but this issue has not been addressed with intracellular techniques. Paired recordings were used to assess the impact of cortical epileptiform activity on striatal neurons in brain slices. Bath-application of 4-amynopyridine (100 microM) and bicuculline (20 microM) induced synchronized bursts in all pairs of cortical neurons (< or = 5 mm apart) in coronal, sagittal, and oblique slices (which preserve connections from the medial agranular cortex to the striatum). Under these conditions, striatal medium spiny neurons (MSs) displayed a strong increased spontaneous glutamatergic activity. This activity was not correlated to the cortical bursts and was asynchronous in pairs of MSs. Sporadic, large-amplitude synchronous depolarizations also occurred in MSs. These events were simultaneously detected in glial cells, suggesting that they were accompanied by considerable increases in extracellular potassium. In oblique slices, cortically driven bursts were also observed in MSs. These events were synchronized to cortical epileptiform bursts, depended on non-N-methyl-D-aspartate (NMDA) glutamate receptors, and persisted in the cortex, but not in the striatum, after disconnection of the two structures. During these bursts, MS membrane potential shifted to a depolarized value (59 +/- 4 mV) on which an irregular waveform, occasionally eliciting spikes, was superimposed. Thus synchronous activation of a limited set of corticostriatal afferents can powerfully control MSs. Cholinergic interneurons located < 120 microm from simultaneously recorded MSs, did not display cortically driven bursts, suggesting that these cells are much less easily engaged by cortical epileptiform activity.

4-Aminopyridine↗

PubMed2004

Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism.

The NMDA receptor complex represents a key molecular element in the pathogenesis of long-term synaptic changes and motor abnormalities in Parkinson's disease (PD). Here we show that NMDA receptor 1 (NR1) subunit and postsynaptic density (PSD)-95 protein levels are selectively reduced in the PSD of dopamine (DA)-denervated striata. These effects are accompanied by an increase in striatal levels of alphaCa2+-calmodulin-dependent protein kinase II (alphaCaMKII) autophosphorylation, along with a higher recruitment of activated alphaCaMKII to the regulatory NMDA receptor NR2A-NR2B subunits. Acute treatment of striatal slices with R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, but not with l-sulpiride, mimicked the effect of DA denervation on both alphaCaMKII autophosphorylation and corticostriatal synaptic plasticity. In addition to normalizing alphaCaMKII autophosphorylation levels as well as assembly and anchoring of the kinase to the NMDA receptor complex, intrastriatal administration of the CaMKII inhibitors KN-93 (N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide) and antennapedia autocamtide-related inhibitory peptide II is able to reverse both the alterations in corticostriatal synaptic plasticity and the deficits in spontaneous motor behavior that are found in an animal model of PD. The same beneficial effects are produced by a regimen of l-3,4-dihydroxyphenylalanine (L-DOPA) treatment, which is able to normalize alphaCaMKII autophosphorylation. These data indicate that abnormal alphaCaMKII autophosphorylation plays a causal role in the alterations of striatal plasticity and motor behavior that follow DA denervation. Normalization of CaMKII activity may be an important underlying mechanism of the therapeutic action of L-DOPA in PD.

Animals↗

PubMed2004

Therapeutic doses of L-dopa reverse hypersensitivity of corticostriatal D2-dopamine receptors and glutamatergic overactivity in experimental parkinsonism.

Levodopa (l-dopa) therapy is still considered the gold-standard in the treatment of Parkinson's disease. However, the synaptic and cellular mechanisms involved in the amelioration of motor symptoms during this treatment are still unclear. To address this issue, we analysed the physiological and pharmacological properties of striatal glutamatergic and GABAergic synaptic transmission in an experimental model of Parkinson's disease. Single-cell recordings were performed in sham-operated rats, in 6-hydroxydopamine-lesioned animals and in rats receiving chronic l-dopa treatment following dopamine (DA) denervation. We utilized a dose of l-dopa (10 mg/kg, twice daily for 21 days) able to reverse motor deficits in about half of parkinsonian animals. In the striatum of parkinsonian animals showing therapeutic benefits following l-dopa treatment, we observed a reversal of glutamatergic overactivity and of the hypersensitivity of presynaptic D2 DA receptors controlling glutamate release from corticostriatal terminals. Conversely, no change was detected in the sensitivity of presynaptic D2 DA receptors modulating striatal GABA transmission in both parkinsonian and l-dopa-treated rats. We suggest that the reversal of striatal glutamatergic overactivity and the normalization of hypersensitive D2 DA receptors modulating excitatory transmission might underlie some of the therapeutic actions of l-dopa in Parkinson's disease.

Animals↗

PubMed2004

Levetiracetam protects against kainic acid-induced toxicity.

We investigated the Levetiracetam (LVT) ability to protect the brain against kainic acid (KA) induced neurotoxicity. Brain injury was induced by intraperitoneal administration of KA (10 mg/kg). Sham brain injury rats were used as controls. Animals were randomized to receive either LVT (50 mg/kg) or its vehicle (1 ml/kg) 30 min. before KA administration. Animals were sacrificed 6 hours after KA injection to measure brain malonildialdehyde (MDA), glutathione levels (GSH) and the mRNA for interleukin-1beta (IL-1beta) in the cortex and in the diencephalon. Behavioral changes were also monitored. Intraperitoneal administration of LVT decreased significantly MDA in the cortex (KA + vehicle = 0.25 +/- 0.03 nmol/mg protein; KA + LVT = 0.13 +/- 0.01 nmol/mg protein; P < 0.005), and in the diencephalons (KA + vehicle = 1,01 +/- 0.2 nmol/mg protein; KA + LVT = 0,33 +/- 0,08 nmol/mg protein; P < 0.005), prevented the brain loss of GSH in both cortex (KA + vehicle = 5 +/- 1 micromol/g protein; KA + LVT = 15 +/- 2 micromol/g protein; P < 0.005) and diencephalons (KA + vehicle = 9 +/- 0.8 micromol/g protein; KA + LVT = 13 +/- 0.3 micromol/g protein; P < 0.05), reduced brain IL-1beta mRNA and markedly controlled seizures. Histological analysis showed a reduction of cell damage in LVT treated samples. The present data indicate that LVT displays neuro-protective effects against KA induced brain toxicity and suggest that these effects are mediated, at least in part, by inhibition of lipid peroxidation.

Animals↗

PubMed2004

Coactivation of GABA(A) and GABA(B) receptor results in neuroprotection during in vitro ischemia.

BACKGROUND AND PURPOSE: The possible neuroprotective effect of endogenous gamma-aminobutyric acid (GABA) on the irreversible electrophysiological changes induced by in vitro ischemia on striatal neurons was investigated. In particular, the aim of the study was the characterization of the neuroprotective action of 2 antiepileptic drugs increasing GABAergic transmission such as tiagabine, a GABA transporter inhibitor, and vigabatrin, an irreversible inhibitor of GABA transaminase. METHODS: Extracellular field potential recordings were obtained from rat corticostriatal slice preparations. In vitro ischemia was delivered by switching to an artificial cerebrospinal fluid solution in which glucose was omitted and oxygen was replaced with N(2). RESULTS: An irreversible loss of the field potentials recorded from striatal neurons was observed after 10 minutes of ischemia in control solution. Conversely, tiagabine and vigabatrin partially prevented the ischemia-induced field potential loss. Surprisingly, both GABA(A) and GABA(B) receptor antagonists blocked these effects. Accordingly, neuroprotection could be obtained only when GABA(A) and GABA(B) receptor agonists were coapplied, but not when a single agonist was given in isolation. CONCLUSIONS: Antiepileptic drugs targeting GABAergic transmission can exert neuroprotective effects against ischemia by increasing endogenous GABA levels and via the activation of both GABA(A) and GABA(B) receptors.

4-Aminobutyrate Transaminase↗

PubMed2004

The Project for a Scientific Psychology (1895): a Freudian anticipation of LTP-memory connection theory.

Long-term potentiation (LTP) of synaptic transmission is considered a reliable cellular model of several forms of learning and memory. Described for the first time in 1973, this synaptic phenomenon consists in the enduring facilitation of the communication between two neurons in response to the sustained activation of the synapses by which they are interconnected. In a book of 1895 entitled Project for a Scientific Psychology, Sigmund Freud theorized about the possibility of representing memory at the synaptic level as "a permanent alteration following an event", and anticipated several crucial physiological properties of LTP. In the present article we aim at presenting Freudian theory on the functional organization of the nervous system developed in the Project, with particular respect to his ideas of the cellular bases of memory.

Animals↗

PubMed2004

Neuronal vulnerability following inhibition of mitochondrial complex II: a possible ionic mechanism for Huntington's disease.

An impaired complex II (succinate dehydrogenase, SD) striatal mitochondrial activity is one of the prominent metabolic alterations in Huntington's disease (HD), and intoxication with 3-nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II, mimics the motor abnormalities and the pathology of HD. We found that striatal spiny neurons responded to this toxin with an irreversible membrane depolarization/inward current, while cholinergic interneurons showed a hyperpolarization/outward current. Both these currents were sensitive to intracellular concentration of ATP. The 3-NP-induced depolarization was associated with an increased release of endogenous GABA, while acetylcholine levels were reduced. Moreover, 3-NP induced a higher depolarization in presymptomatic R6/2 HD transgenic mice compared to wild-type (WT) mice, showing an increased susceptibility to SD inhibition. Conversely, the hyperpolarization did not significantly differ from the one recorded in WT mice. The diverse membrane changes induced by SD inhibition may contribute to the cell-type-specific neuronal death in HD.

Acetylcholine↗

PubMed2004

Inhibition of mitochondrial complex II alters striatal expression of genes involved in glutamatergic and dopaminergic signaling: possible implications for Huntington's disease.

Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by motor abnormalities and cognitive impairment. The irreversible succinate dehydrogenase (SD) inhibitor 3-nitropropionic acid (3NP) causes neurodegeration in the striatum resembling HD when administered to rodents or primates. Using corticostriatal brain slice preparations, we analyzed the pattern of gene expression following 3NP application utilizing cDNA microarrays. Acute 3NP treatment modulates the expression of several genes involved in dopaminergic and glutamatergic signaling in corticostriatal brain slices, and unbalances the downstream serine/threonine protein kinase and phosphatase network affecting the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). Our data provide new information about the molecular events possibly underlying neurodegeneration induced by this mitochondrial toxin.

Animals↗