Receptor and post-receptor mechanisms of ischemic long-term potentiation in the striatum.
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Animals↗
Biomedical subjects
P Calabresi
Publications and source records attributed to P Calabresi.
Dopamine and cAMP-regulated phosphoprotein 32 kDa controls both striatal long-term depression and long-term potentiation, opposing forms of synaptic plasticity.
A complex chain of intracellular signaling events, critically important in motor control, is activated by the stimulation of D1-like dopamine (DA) receptors in striatal neurons. At corticostriatal synapses on medium spiny neurons, we provide evidence that the D1-like receptor-dependent activation of DA and cyclic adenosine 3',5' monophosphate-regulated phosphoprotein 32 kDa is a crucial step for the induction of both long-term depression (LTD) and long-term potentiation (LTP), two opposing forms of synaptic plasticity. In addition, formation of LTD and LTP requires the activation of protein kinase G and protein kinase A, respectively, in striatal projection neurons. These kinases appear to be stimulated by the activation of D1-like receptors in distinct neuronal populations.
Action Potentials↗
Cellular factors controlling neuronal vulnerability in the brain: a lesson from the striatum.
In many acute and chronic neurologic disorders, both deficits in energy metabolism and defects in glutamate-mediated excitatory synaptic transmission have been proposed as important pathogenic factors. Brain cells, however, express variable vulnerability to these insults, as indicated by the fact that certain brain areas and even different cell types in the same area are preferentially spared until the very late stages of various diseases. This can be clearly seen in the striatum, where GABAergic projection cells but not cholinergic interneurons are precociously damaged in the course of both acute metabolic insults (such as hypoxia, hypoglycemia, and ischemia) and chronic neurodegenerative disorders (such as Huntington's disease). A well-mapped pattern of cell loss, in fact, is a common finding in the striatum of patients suffering from these pathologic conditions. Physiologic and molecular studies have been directed in recent years to the identification of the cellular mechanisms underlying the cell-type specific vulnerability of striatal cells. These studied recognized that, in striatal spiny and aspiny cells, specific membrane ion channels, glutamate receptor subtypes and subunits, and intracellular enzymatic activities are involved in the cascade of events responsible for opposite responses and vulnerabilities to oxygen or glucose deprivation and to glutamate receptor-mediated toxicity. Specific molecules able to target these cellular factors might be employed as therapeutic agents during acute and chronic neurologic disorders affecting this brain area.
Corpus Striatum↗
Activation of D2-like dopamine receptors reduces synaptic inputs to striatal cholinergic interneurons.
Dopamine (DA) plays a crucial role in the modulation of striatal function. Striatal cholinergic interneurons represent an important synaptic target of dopaminergic fibers arising from the substantia nigra and cortical glutamatergic inputs. By means of an electrophysiological approach from corticostriatal slices, we isolated three distinct synaptic inputs to cholinergic interneurons: glutamate-mediated EPSPs, GABAA-mediated potentials, and Acetylcholine (ACh)-mediated IPSPs. We therefore explored whether DA controls the striatal cholinergic activity through the modulation of these synaptic potentials. We found that SKF38393, a D1-like receptor agonist, induced a membrane depolarization (also see Aosaki et al., 1998) but had no effects on glutamatergic, GABAergic, and cholinergic synaptic potentials. Conversely, D2-like DA receptor activation by quinpirole inhibited both GABAA and cholinergic synaptic potentials. These effects of quinpirole were mimicked by omega-conotoxin GVIA, blocker of N-type calcium channels. The lack of effect both on the intrinsic membrane properties and on exogenously applied GABA and ACh by quinpirole supports a presynaptic site of action for the D2-like receptor-mediated inhibition. Moreover, the quinpirole-induced decrease in amplitude was accompanied by an increase in paired pulse facilitation ratio (EPSP2/EPSP1), an index of a decrease in transmitter release. Our findings demonstrate that DA modulates the excitability of cholinergic interneurons through either an excitatory D1-like-mediated postsynaptic mechanism or a presynaptic inhibition of the GABAergic and cholinergic inhibitory synaptic potentials.
Acetylcholine↗
Electrophysiology of sipatrigine: a lamotrigine derivative exhibiting neuroprotective effects.
Sipatrigine (BW619C89), a derivative of the antiepileptic agent lamotrigine, has potent neuroprotective properties in animal models of cerebral ischemia and head injury. In the present study we investigated the electrophysiological effects of sipatrigine utilizing intracellular current-clamp recordings obtained from striatal spiny neurons in rat corticostriatal slices and whole-cell patch-clamp recordings in isolated striatal neurons. The number of action potentials produced in response to a depolarizing current pulse in the recorded neurons was reduced by sipatrigine (EC(50) 4.5 microM). Although this drug preferentially blocked action potentials in the last part of the depolarizing current pulse, it also decreased the frequency of the first action potentials. Sipatrigine also inhibited tetrodotoxin-sensitive sodium (Na(+)) current recorded from isolated striatal neurons. The EC(50) for this inhibitory action was 7 microM at the holding potential (V(h)) of -65 mV, but 16 microM at V(h) = -105, suggesting a dependence of this pharmacological effect on the membrane potential. Moreover, although the inhibitory action of sipatrigine on Na(+) currents was maximal during high-frequency activation (20 Hz), it could also be detected at low frequencies. The amplitude of excitatory postsynaptic potentials (EPSPs), recorded following stimulation of the corticostriatal pathway, was depressed by sipatrigine (EC(50) 2 microM). This inhibitory action, however, was incomplete; in fact maximal concentrations of this drug reduced EPSP amplitude by only 45%. Sipatrigine produced no increase in paired-pulse facilitation, suggesting that the modulation of a postsynaptic site was the main pharmacological effect of this agent. The inhibition of voltage-dependent Na(+) channels exerted by sipatrigine might account for its depressant effects on both repetitive firing discharge and corticostriatal excitatory transmission. The modulation of Na(+) channels described here, as well as the previously observed inhibition of high-voltage-activated calcium currents, might contribute to the neuroprotective efficacy exerted by this compound in experimental models of in vitro and in vivo ischemia.
Action Potentials↗
Cell-type specificity of mGluR activation in striatal neuronal subtypes.
The effects of metabotropic glutamate receptor (mGluR) activation were studied in medium spiny neurons and large aspiny (LA) interneurons by means of electrophysiological and optical recordings. DCG-IV and L-SOP, agonists for group II and III mGluRs, respectively, produced a presynaptic inhibitory effect on corticostriatal glutamatergic excitatory postsynaptic potentials (EPSPs) in both spiny and LA cells. Activation of group I mGluRs by the selective agonist 3,5-DHPG produced no effect on membrane properties and glutamatergic transmission in spiny neurons, whereas it did cause a membrane depolarization in LA interneurons coupled to increased input resistance. In combined optical and electrophysiological experiments, in spiny neurons 3,5-DHPG enhanced membrane depolarization and intracellular calcium (Ca2+) levels induced by NMDA applications, but not in LA interneurons. These data suggest the existence of a positive interaction between NMDA and group I mGlu receptors only in medium spiny cells which might, at least partially, account for the differential vulnerability to excitotoxic damage observed in striatal neuronal subtypes.
Animals↗
Amifostine cytotoxicity and induction of apoptosis in a human myelodysplastic cell line.
Amifostine (AMF), a phosphorylated aminothiol, has been used to treat myelodysplastic syndrome (MDS), where it produces a stimulatory effect on hematopoiesis in bone marrow. To determine if AMF also produced a direct effect on human MDS cells, we planned a study to evaluate the effect of a continuous exposure to AMF on a human MDS cell line. AMF was shown to have a growth-inhibitory effect on MDS cells, with an IC(50) of 14 microM after a 5 day exposure. Cell cycle analysis revealed that a 5 day exposure to 20 microM AMF increased the percentage of cells in G0/G1 and this was accompanied by a decrease in the percentage of cells in S phase. Cytoflorometric and agarose-gel electrophoretic analysis revealed that this effect correlated with cell membrane alterations and DNA fragmentation consistent with an induction of apoptosis without affecting the expression of p53 protein or inducing any lymphoid or myeloid differentiation in the MDS cell line. We conclude that the continuous exposure of a human MDS cell line to AMF is cytotoxic and associated with an induction of apoptosis independent of alterations in p53 expression.
Amifostine↗
Acetylcholine-mediated modulation of striatal function.
Striatal spiny neurones serve as a major anatomical locus for the relay of cortical information flow through the basal ganglia. these projection neurones also represent the main synaptic target of cholinergic interneurones, whose physiological role in striatal activity still remains largely enigmatic. The striatal cholinergic system has been implicated in the pathophysiology of movement disorders such as Parkinson's disease, but the cellular mechanisms underlying cholinergic-neurone function are still unknown. On the basis of in vitro electrophysiological evidence, obtained from a rat corticostriatal-slice preparation, we propose that endogenous ACh exerts a complex modulation of striatal synaptic transmission, which produces both short-term and long-term effects. ACh-mediated mechanisms might be of crucial importance in processing the cortical inputs to the striatum.
Acetylcholine↗
Synaptic transmission in the striatum: from plasticity to neurodegeneration.
Striatal neurones receive myriad of synaptic inputs originating from different sources. Massive afferents from all areas of the cortex and the thalamus represent the most important source of excitatory amino acids, whereas the nigrostriatal pathway and intrinsic circuits provide the striatum with dopamine, acetylcholine, GABA, nitric oxide and adenosine. All these neurotransmitter systems interact each other and with voltage-dependent conductances to regulate the efficacy of the synaptic transmission within this nucleus. The integrative action exerted by striatal projection neurones on this converging information dictates the final output of the striatum to the other basal ganglia structures. Recent morphological, immunohistochemical and electrophysiological findings demonstrated that the striatum also contains different interneurones, whose role in physiological and pathological conditions represents an intriguing challenge in these years. The use of the in vitro brain slice preparation has allowed not only the detailed investigation of the direct pre- and postsynaptic electrophysiological actions of several neurotransmitters in striatal neurones, but also the understanding of their role in two different forms of corticostriatal synaptic plasticity, long-term depression and long-term potentiation. These long-lasting changes in the efficacy of excitatory transmission have been proposed to represent the cellular basis of some forms of motor learning and are altered in animal models of human basal ganglia disorders, such as Parkinson's disease. The striatum also expresses high sensitivity to hypoxic-aglycemic insults. During these pathological conditions, striatal synaptic transmission is altered depending on presynaptic inhibition of transmitter release and opposite membrane potential changes occur in projection neurones and in cholinergic interneurones. These ionic mechanisms might partially explain the selective neuronal vulnerability observed in the striatum during global ischemia and Huntington's disease.
Animals↗
Electrophysiology of dopamine in normal and denervated striatal neurons.
Parkinson's disease (PD) symptoms originate from the loss of the dopaminergic control of neuronal activity in the striatum. Permanent loss of dopaminergic terminals in the striatum results in an abnormal activity of striatal neurons. The therapeutic treatment with exogenous dopamine, therefore, temporarily restores a balanced synaptic excitation of striatal neurons, counteracting pre- and postsynaptically the excessive glutamate release caused by the degeneration of nigrostriatal dopaminergic fibers. However, chronic treatment is associated with adverse effects that might reflect nonphysiological dopamine replacement. Basic studies on experimental animal models of PD are of crucial importance for the development of therapeutic agents able to provide relief to individuals with PD, without the adverse effects associated with currently available drugs.
Animals↗
Tissue plasminogen activator controls multiple forms of synaptic plasticity and memory.
Induction of long-term depression (LTD) in rat striatal slices revealed that this form of synaptic plasticity is coupled to an increased expression of tissue-plasminogen activator (t-PA) mRNA, as detected by the mRNA differential display technique. To further investigate the involvement of this gene in synaptic remodelling following striatal LTD, we recorded electrical activity from mice lacking the gene encoding t-PA (t-PA-KO) and from wild-type (WT) mice. Tetanic stimulation induced LTD in the large majority of striatal neurons recorded from WT mice. Conversely, LTD was absent in a significant proportion of striatal neurons obtained from mice lacking t-PA. Electrophysiological recordings obtained from hippocampal slices in the CA1 area showed that mainly the late phase of long-term potentiation (LTP) was reduced in t-PA-KO mice. Learning and memory-related behavioural abnormalities were also found in these transgenic mice. Disruption of the t-PA gene, in fact, altered both the context conditioning test, a hippocampus-related behavioural task, and the two-way active avoidance, a striatum-dependent task. In an open field object exploration task, t-PA-KO mice expressed deficits in habituation and reactivity to spatial change that are consistent with an altered hippocampal function. Nevertheless, decreased rearing and poor initial object exploration were also observed, further suggesting an altered striatal function. These data indicate that t-PA plays a critical role in the formation of various forms of synaptic plasticity and memory.
Animals↗
Involvement of intracellular calcium stores during oxygen/glucose deprivation in striatal large aspiny interneurons.
Striatal large aspiny interneurons were recorded from a slice preparation using a combined electrophysiologic and microfluorometric approach. The role of intracellular Ca2+ stores was analyzed during combined oxygen/glucose deprivation (OGD). Before addressing the role of the stores during energy deprivation, the authors investigated their function under physiologic conditions. Trains of depolarizing current pulses caused bursts of action potentials coupled to transient increases in intracellular calcium concentration ([Ca2+]i). In the presence of cyclopiazonic acid (30 micromol/L), a selective inhibitor of the sarcoendoplasmic reticulum Ca2+ pumps, or when ryanodine receptors were directly blocked with ryanodine (20 [micromol/L), the [Ca2+]i transients were progressively smaller in amplitude, suggesting that [Ca2+]i released from intracellular stores helps to maintain a critical level of [Ca2+]i during physiologic firing activity. As the authors have recently reported, brief exposure to combined OGD induced a membrane hyperpolarization coupled to an increase in [Ca2+]i. In the presence of cyclopiazonic acid or ryanodine, the hyperpolarization and the rise in [Ca2+]i induced by OGD were consistently reduced. These data support the hypothesis that Ca2+ release from ryanodine-sensitive Ca2+ pools is involved not only in the potentiation of the Ca2+ signals resulting from cell depolarization, but also in the amplification of the [Ca2+]i rise and of the concurrent membrane hyperpolarization observed in course of OGD in striatal large aspiny interneurons.
Animals↗
Is pharmacological neuroprotection dependent on reduced glutamate release?
BACKGROUND AND PURPOSE: The aim of this study was to determinate the possible role of the ionotropic glutamate receptor in the expression of irreversible electrophysiological changes induced by in vitro ischemia and to test whether the neuroprotective action of various neurotransmitter agonists and drugs of clinical interest is related to a presynaptic inhibitory action at glutamatergic synapses. METHODS: Intracellular and extracellular recordings have been performed in a rat corticostriatal slice preparation. Different pharmacological compounds have been tested on corticostriatal glutamatergic transmission in control conditions and in an in vitro model of ischemia (oxygen and glucose deprivation). RESULTS: In vitro ischemia lasting 10 minutes produced an irreversible loss of the field potential recorded from striatal slices after cortical stimulation. Preincubation of the slices with 3 micromol/L 6-cyano-7-nitroquinoxaline-2,3-dione (an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA] receptor antagonist) allowed a significant recovery of the field potential amplitude (P<0.05, n=6), whereas incubation with 30 micromol/L aminophosphonovaleric acid (an N-methyl-D-aspartate receptor antagonist) did not produce a significant recovery after 10 minutes of ischemia (P>0.05, n=7). Bath application of 3 mmol/L glutamate for 5 minutes produced a complete but reversible inhibition of the field potential amplitude. When a similar application was coupled with a brief period of ischemia (5 minutes), which produced, per se, only a transient inhibition of the field potential, it caused an irreversible loss of this parameter. We also tested the possible neuroprotective effect of neurotransmitter agonists reducing the release of glutamate from corticostriatal terminals. Agonists acting on purinergic (adenosine), muscarinic (oxotremorine), and metabotropic glutamate receptors (L-serine o-phosphate [L-SOP]) significantly (P<0.001, n=8 for each agonist) reduced glutamatergic synaptic potentials, with each showing different potencies. The EC(50) was 26.4 micromol/L for adenosine, 0. 08 micromol/L for oxotremorine, and 0.89 micromol/L for L-SOP. Concentrations of these agonists producing the maximal inhibition of the synaptic potential were tested on the ischemia-induced irreversible loss of field potential. Adenosine (P<0.05, n=9) and oxotremorine (P<0.05, n=8) showed significant neuroprotective action, whereas L-SOP was ineffective (P>0.05, n=10). Similarly, putative neuroprotective drugs significantly (P<0.001, n=10 for each drug) reduced the amplitude of corticostriatal potential, with different EC(50) values (phenytoin, 33.5 micromol/L; gabapentin, 96.8 micromol/L; lamotrigine, 26.7 micromol/L; riluzole, 6 micromol/L; and sipatrigine, 2 micromol/L). Concentration of these drugs producing maximal inhibition of the amplitude of corticostriatal potentials showed a differential neuroprotective action on the ischemic electrical damage. Phenytoin (P<0.05, n=10), lamotrigine (P<0.05, n=10), riluzole (P<0.05, n=9), and sipatrigine (P<0.001, n=10) produced a significant neuroprotection, whereas gabapentin (P>0.05, n=11) was ineffective. The neuroprotective action of transmitter agonists and clinical drugs was not related to their ability in decreasing glutamate release, as detected by changes in the paired-pulse facilitation protocol. CONCLUSIONS: Ionotropic glutamate receptors, and particularly AMPA-like receptors, play a role in the irreversible loss of field potential amplitude induced by ischemia in the striatum. Drugs acting by reducing glutamatergic corticostriatal transmission may show a neuroprotective effect. However, their efficacy does not seem to be directly related to their capability to decrease glutamate release from corticostriatal terminals. We suggest that additional modulatory actions on voltage-dependent conductances and on ischemia-induced ion distribution at the postsynaptic site may also exert a crucial role.
Action Potentials↗
Levodopa-induced dyskinesia: a pathological form of striatal synaptic plasticity?
The pathogenesis of the alterations in motor response that complicate levodopa therapy of Parkinson's disease remains obscure. Several experimental and clinical observations strongly suggest that changes in striatal activity may be crucial for this physiopathological condition. Accordingly, it has been postulated that dyskinesia might be due to abnormal activity of the corticostriatal pathway. Here, we review the physiological and pharmacological mechanisms underlying glutamatergic regulation of striatal neurons by the corticostriatal projection. In particular, we discuss the role of both (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors in the control of the short- and long-term efficacy of corticostriatal transmission. Indeed, repetitive cortical activation can generate either long-term depression or long-term potentiation (LTP) at corticostriatal synapses depending on the subtype of glutamate receptor activated during the induction phase of these forms of synaptic plasticity. Dopamine plays an important function in the regulation of both forms of synaptic plasticity. Dopamine denervation abolishes the physiological corticostriatal plasticity by producing biochemical and morphological changes within the striatum. We have recently observed a 'pathological' form of LTP at the corticostriatal synapse during energy deprivation. We speculate that this 'pathological' LTP, depending on the activation of NMDA glutamate receptors located on spiny striatal neurons, might play a role in the generation of levodopa-induced dyskinesia.
Dopamine Agents↗
Medical alternatives to alternative medicine.
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Complementary Therapies↗
Modulation of gene expression following long-term synaptic depression in the striatum.
A number of behavioural and cellular studies have suggested that activity-dependent synaptic plasticity associated with learning and memory may lead to the expression of various genes whose protein products can play a critical role in memory acquisition and consolidation. Long-term potentiation (LTP) and long-term depression (LTD) represent two forms of synaptic plasticity which have been widely studied by electrophysiological techniques. However, the molecular mechanisms at target gene involved in the generation of long term depression remain to be determined. To elucidate the molecular mechanism underlying activity dependent synaptic remodeling in striatal long term depression, we used the mRNA differential display technology to isolate genes that are induced or modulated by high frequency stimulation of the corticostriatal pathway in a rat brain slice preparation. We have differentially displayed, by means of reverse transcriptase-polymerase chain reaction, mRNA species isolated from striatal slices in which long term depression was induced by tetanic stimuli as well as from slices stimulated at low frequency. We then compared radio-labeled RT-PCR banding patterns to isolate cDNAs that are differentially expressed. Three independent cDNAs were isolated and identified whose mRNA level were enhanced by tetanic stimulation inducing long term depression. We provide evidence that two of these genes encode proteins involved in synaptic vesicle trafficking (dynamin I and amphiphysin II). Moreover, expression of tissue plasminogen activator (t-PA) gene was also increased following striatal long term depression. Our data suggest that a complex pattern of genes acting at presynaptic level and extracellularly may be involved in LTD-associated synaptic remodeling.
Animals↗
Glutamate-triggered events inducing corticostriatal long-term depression.
Repetitive activation of corticostriatal fibers produces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of synaptic plasticity might be considered the possible neural basis of some forms of motor learning and memory. In the present study, intracellular recordings were performed from rat corticostriatal slice preparations to study the role of glutamate and other critical factors underlying striatal LTD. In current-clamp, but not in voltage-clamp experiments, brief focal applications of glutamate, as well as high-frequency stimulation (HFS) of corticostriatal fibers, induced LTD. This pharmacological LTD and the HFS-induced LTD were mutually occlusive, suggesting that both forms of synaptic plasticity share common induction mechanisms. Isolated activation of either non-NMDA-ionotropic glutamate receptors (iGluRs) or metabotropic glutamate receptors (mGluRs), respectively by AMPA and t-ACPD failed to produce significant long-term changes of corticostriatal synaptic transmission. Conversely, LTD was obtained after the simultaneous application of AMPA plus t-ACPD. Moreover, also quisqualate, a compound that activates both iGluRs and group I mGluRs, was able to induce this form of pharmacological LTD. Electrical depolarization of the recorded neurons either alone or in the presence of t-ACPD and dopamine (DA) failed to mimic the effects of the activation of glutamate receptors in inducing LTD. However, electrical depolarization was able to induce LTD when preceded by coadministration of t-ACPD, DA, and a low dose of hydroxylamine, a compound generating nitric oxide (NO) in the tissue. None of these compounds alone produced LTD. Glutamate-induced LTD, as well as the HFS-induced LTD, was blocked by L-sulpiride, a D2 DA receptor antagonist, and by 7-nitroindazole monosodium salt, a NO synthase inhibitor. The present study indicates that four main factors are required to induce corticostriatal LTD: (1) membrane depolarization of the postsynaptic neuron; (2) activation of mGluRs; (3) activation of DA receptors; and (4) release of NO from striatal interneurons.
Animals↗
A critical role of the nitric oxide/cGMP pathway in corticostriatal long-term depression.
High-frequency stimulation (HFS) of corticostriatal glutamatergic fibers induces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of LTD can be mimicked by zaprinast, a selective inhibitor of cGMP phosphodiesterases (PDEs). Biochemical analysis shows that most of the striatal cGMP PDE activity is calmodulin-dependent and inhibited by zaprinast. The zaprinast-induced LTD occludes further depression by tetanic stimulation and vice versa. Both forms of synaptic plasticity are blocked by intracellular 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase, indicating that an increased cGMP production in the spiny neuron is a key step. Accordingly, intracellular cGMP, activating protein kinase G (PKG), also induces LTD. Nitric oxide synthase (NOS) inhibitors N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) and 7-nitroindazole monosodium salt (7-NINA) block LTD induced by either HFS or zaprinast, but not that induced by cGMP. LTD is also induced by the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and hydroxylamine. SNAP-induced LTD occludes further depression by HFS or zaprinast, and it is blocked by intracellular ODQ but not by L-NAME. Intracellular application of PKG inhibitors blocks LTD induced by HFS, zaprinast, and SNAP. Electron microscopy immunocytochemistry shows the presence of NOS-positive terminals of striatal interneurons forming synaptic contacts with dendrites of spiny neurons. These findings represent the first demonstration that the NO/cGMP pathway exerts a feed-forward control on the corticostriatal synaptic plasticity.
Animals↗