Lydia Kerkerian-Le Goff

Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both.

High-frequency deep brain stimulation (DBS) of the thalamus or basal ganglia represents an effective clinical technique for the treatment of several medically refractory movement disorders. However, understanding of the mechanisms responsible for the therapeutic action of DBS remains elusive. The goal of this review is to address our present knowledge of the effects of high-frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS. Four general hypotheses have been developed to explain the mechanism(s) of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathological network activity. Using the results from functional imaging, neurochemistry, neural recording, and neural modeling experiments we address the general hypotheses and attempt to reconcile what have been considered conflicting results from these different research modalities. Our analysis suggests stimulation-induced modulation of pathological network activity represents the most likely mechanism of DBS; however, several open questions remain to explicitly link the effects of DBS with therapeutic outcomes.

Deep brain stimulation in neurological diseases and experimental models: from molecule to complex behavior.

Deep brain stimulation (DBS) has proven to be capable of providing significant benefits for several neuropathologies. It is highly effective in reducing the motor symptoms of Parkinsons disease, essential tremor, and dystonia, and in alleviating chronic pain. Recently, also Tourette syndrome, obsessive-compulsive disorder and treatment-resistant depression have been treated by DBS with encouraging results. However, despite these clinical achievements, the precise action mechanisms of DBS still need to be fully characterized. For this reason, several animal models of DBS have been developed, bringing new insights on the effects of this treatment at molecular and cellular level, and providing new evidence on its physiological and behavioral consequences. In parallel, physiological and imaging studies in patients have contributed to better understanding DBS impact on the function of brain circuits. Here we review the clinical data and experimental work in vitro, ex vivo and in vivo (mostly arisen from studies on DBS of the subthalamic nucleus) in the treatment of PD, which led to the actual knowledge of DBS mechanisms, from molecular to complex behavioral levels.

Chronic high‐frequency stimulation of the subthalamic nucleus and L‐DOPA treatment in experimental parkinsonism: effects on motor behaviour and striatal glutamate transmission

Hyperactivity of striatal glutamatergic synaptic transmission in response to dopamine depletion plays a major role in the pathogenesis of parkinsonian motor symptoms. In the present study we investigated the impact, on this hyperactivity, of chronic dyskinesiogenic L‐DOPA treatment, combined or not with high‐frequency stimulation (HFS) of the subthalamic nucleus (STN). In vitro patch‐clamp recordings were performed from striatal spiny neurons of hemiparkinsonian rats (intranigral 6‐OHDA injection). Here we show that dyskinesiogenic L‐DOPA treatment exacerbated striatal glutamatergic hyperactivity induced by 6‐OHDA lesion. Chronic 5‐day STN HFS had the opposite effect, reducing striatal glutamatergic transmission in both parkinsonian and dyskinetic animals. Consistently, chronic HFS stimulation could progressively ameliorate motor parkinsonian signs (akinesia) but, conversely, did not improve L‐DOPA‐induced dyskinesia (LID). Thus, the effects of L‐DOPA and HFS on corticostriatal transmission seem to be dissociated. These data show for the first time that dyskinesiogenic L‐DOPA treatment and chronic STN HFS with antiakinetic effects induce opposite plastic rearrangements in the striatum. The interaction between these two treatments provides further evidence that striatal glutamatergic hyperactivity is a pathophysiological correlate of akinesia rather than LID.

Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate Handling In Vivo

To study the functional role of activated astrocytes in glutamate homeostasis in vivo, we used a model of sustained astrocytic activation in the rat striatum through lentiviral-mediated gene delivery of ciliary neurotrophic factor (CNTF). CNTF-activated astrocytes were hypertrophic, expressed immature intermediate filament proteins and highly glycosylated forms of their glutamate transporters GLAST and GLT-1. CNTF overexpression produced a redistribution of GLAST and GLT-1 into raft functional membrane microdomains, which are important for glutamate uptake. In contrast, CNTF had no detectable effect on the expression of a number of neuronal proteins and on the spontaneous glutamatergic transmission recorded from striatal medium spiny neurons. These results were replicated in vitro by application of recombinant CNTF on a mixed neuron/astrocyte striatal culture. Using microdialysis in the rat striatum, we found that the accumulation of extracellular glutamate induced by quinolinate (QA) was reduced threefold with CNTF. In line with this result, CNTF significantly increased QA-induced [18F]-fluoro-2-deoxyglucose uptake, an indirect index of glutamate uptake by astrocytes. Together, these data demonstrate that CNTF activation of astrocytes in vivo is associated with marked phenotypic and molecular changes leading to a better handling of increased levels of extracellular glutamate. Activated astrocytes may therefore be important prosurvival agents in pathological conditions involving defects in glutamate homeostasis.

High-Frequency Stimulation of the Subthalamic Nucleus Potentiates l-DOPA-Induced Neurochemical Changes in the Striatum in a Rat Model of Parkinson's Disease

This study examined the cellular changes produced in the striatum by chronic l-DOPA treatment and prolonged subthalamic nucleus high-frequency stimulation (STN–HFS) applied separately, successively, or in association, in the 6-hydroxydopamine-lesioned rat model of Parkinsons disease (PD). Only animals showing severe l-DOPA-induced dyskinesias (LIDs) were included, and STN–HFS was applied for 5 d at an intensity efficient for alleviating akinesia without inducing dyskinesias. l-DOPA treatment alone induced FosB/ΔFosB immunoreactivity, exacerbated the postlesional increase in preproenkephalin, reversed the decrease in preprotachykinin, and markedly increased mRNA levels of preprodynorphin and of the glial glutamate transporter GLT1, which were respectively decreased and unaffected by the dopamine lesion. STN–HFS did not affect per se the postlesion changes in any of these markers. However, when applied in association with l-DOPA treatment, it potentiated the positive modulation exerted by l-DOPA on all of the markers examined and tended to exacerbate LIDs. After 5 d of l-DOPA withdrawal, the only persisting drug-induced responses were an elevation in preprodynorphin mRNA levels and in the number of FosB/ΔFosB-immunoreactive neurons. Selective additional increases in these two markers were measured when STN–HFS was applied subsequently to l-DOPA treatment. These data provide the first evidence that STN–HFS exacerbates the responsiveness of striatal cells to l-DOPA medication and suggest that STN–HFS acts specifically through an l-DOPA-modulated signal transduction pathway associated with LIDs in the striatum. They point to striatal cells as a primary site for the complex interactions between these two therapeutic approaches in PD and argue against a direct anti-dyskinetic action of STN–HFS.

Somatostatin-immunoreactive neurons in the rat striatum: effects of corticostriatal and nigrostriatal dopaminergic lesions.

The present study examined the effects of the impairment of corticostriatal and nigrostriatal dopaminergic transmission on the mean number and the topographical distribution of somatostatin-containing neurons in frontal sections of the rat rostral striatum. These neurons, visualized by an immunohistochemical method using a specific anti-somatostatin(28) antibody were shown to be unevenly distributed; the number of immunoreactive perikarya being consistently lower in the dorsolateral and higher in the middle areas of striatal sections than in the remaining parts of the structure. Such a distribution and number were not altered either by unilateral 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal dopaminergic neurons after 2- to 3-week survival periods, or by alpha-methylparatyrosine-induced dopamine depletion. In animals with similar 6-OHDA-induced lesions, no change in the striatal concentration of somatostatin measured by radioimmunoassay was observed. These results suggest that somatostatin levels in striatal neurons are not under a dopaminergic influence in contrast to that previously described for neuropeptide Y, although both peptides are thought to coexist extensively in the same striatal neuron population. On the contrary, extensive unilateral frontoparietal ablation of the cerebral cortex elicited, 2-3 weeks later, a significant increase in the mean number of somatostatin-immunoreactive cells per section in the ipsilateral striatum preferentially localized to the dorsolateral zone of the structure with no change in the contralateral side. Data from immunohistochemical studies were further discussed in comparison with results obtained by radioimmunoassay showing that similar cortical lesion induced no change in somatostatin endogenous levels in the ipsilateral striatum and a 30% decreased concentration of the peptide in the contralateral striatum. These data suggest that the corticostriatal pathway influences the expression of somatostatin at either a translational, processing or metabolic level in a topographically restricted population of striatal somatostatin-containing neurons.

Intracerebroventricular administration of neuropeptide Y affects parameters of dopamine, glutamate and GABA activities in the rat striatum

The effects of intracerebroventricular (ICV) injection of neuropeptide Y (NPY) on parameters of dopamine (DA), glutamate (Glu) and gamma-aminobutyric acid (GABA) activities were investigated in the rat striatum. NPY (1.17-4.70 nmol) induced a dose-dependent increase in the striatal endogenous DA release monitored in freely moving animals by means of a voltammetric method. Maximal increase was observed about one hour after the peptide injection. This result is consistent with the hypothesis that NPY may influence striatal DA turnover in a facilitatory manner by activating DA release. DA, DOPAC, Glu and GABA endogenous contents as well as 3H-Glu and 3H-GABA synaptosomal high affinity uptakes were examined one hour after NPY ICV administration at the same dose range in chloral hydrate-anesthetized animals. Depending on the NPY dose injected, opposite changes in Glu uptake were observed, suggesting that NPY has a bimodal influence on glutamatergic transmission. The Glu uptake rate increased markedly at 1.17 nmol NPY and decreased at 4.70 nmol, which may reflect an activation and an inhibition of the striatal Glu transmission, respectively. In parallel, the GABA uptake was found to decrease slightly at the higher doses of NPY tested, whereas no significant alteration of the striatal concentrations of either DA, DOPAC, Glu or GABA was observed. These results indicate that NPY may be involved in regulating the activity of nigral dopaminergic and cortical glutamatergic afferent pathways and that of intrinsic GABA neurons in the rat striatum.

Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson’s disease treatment

Alterations of striatal synaptic transmission have been associated with several motor disorders involving the basal ganglia, such as Parkinson’s disease. For this reason, we investigated the role of group‐III metabotropic glutamate (mGlu) receptors in regulating synaptic transmission in the striatum by electrophysiological recordings and by using our novel orthosteric agonist (3S)‐3‐[(3‐amino‐3‐carboxypropyl(hydroxy)phosphinyl)‐hydroxymethyl]‐5‐nitrothiophene (LSP1‐3081) and l‐2‐amino‐4‐phosphonobutanoate (L‐AP4). Here, we show that both drugs dose‐dependently reduced glutamate‐ and GABA‐mediated post‐synaptic potentials, and increased the paired‐pulse ratio. Moreover, they decreased the frequency, but not the amplitude, of glutamate and GABA spontaneous and miniature post‐synaptic currents. Their inhibitory effect was abolished by (RS)‐α‐cyclopropyl‐4‐phosphonophenylglycine and was lost in slices from mGlu4 knock‐out mice. Furthermore, (S)‐3,4‐dicarboxyphenylglycine did not affect glutamate and GABA transmission. Finally, intrastriatal LSP1‐3081 or L‐AP4 injection improved akinesia measured by the cylinder test. These results demonstrate that mGlu4 receptor selectively modulates striatal glutamate and GABA synaptic transmission, suggesting that it could represent an interesting target for selective pharmacological intervention in movement disorders involving basal ganglia circuitry.

Glutamate transport alteration triggers differentiation-state selective oxidative death of cultured astrocytes: a mechanism different from excitotoxicity depending on intracellular GSH contents

Recent evidence has been provided for astrocyte degeneration in experimental models of neurodegenerative insults associated with glutamate transport alteration. To determine whether astrocyte death can directly result from altered glutamate transport, we here investigated the effects of l‐trans‐pyrrolidine‐2,4‐dicarboxylate (PDC) on undifferentiated or differentiated cultured rat striatal astrocytes. PDC induced death of differentiated astrocytes without affecting undifferentiated astrocyte viability. Death of differentiated astrocytes was also triggered by another substrate inhibitor but not by blockers of glutamate transporters. The PDC‐induced death was delayed and apoptotic, and death rate was dose and treatment duration‐dependent. Although preceded by extracellular glutamate increase, this death was not mediated through glutamate receptor stimulation, as antagonists did not provide protection. It involves oxidative stress, as a decrease in glutathione contents and a dramatic raise in reactive oxygen species preceded cell loss, and as protection was provided by antioxidants. PDC induced a similar percentage of GSH depletion in the undifferentiated astrocytes, but only a slight increase in reactive oxygen species. Interestingly, undifferentiated astrocytes exhibited twofold higher basal GSH content compared with the differentiated ones, and depleting their GSH content was found to render them susceptible to PDC. Altogether, these data demonstrate that basal GSH content is a critical factor of astrocyte vulnerability to glutamate transport alteration with possible insights onto concurrent death of astrocytes and gliosis in neurodegenerative insults.

Region- and phase-dependent effects of 5-HT1A and 5-HT2C receptor activation on adult neurogenesis

Adult neurogenesis and serotoninergic transmission are associated to mood disorders and their treatments. The present study focused on the effects of chronic activation of 5-HT(1A) and 5-HT(2C) receptors on newborn cell survival in the dentate gyrus (DG) and olfactory bulb (OB), and examined whether potential neurogenic zones as the prefrontal cortex (PFC) and striatum (ST) are reactive to these treatments. Administration of 8-OH-DPAT, but not RO600,175 increases neurogenesis and survival of late differentiating cells (15-21days) in the DG. Both 8-OH-DPAT and RO600,175 increase neurogenesis in the OB, but only 8-OH-DPAT affected cell survival, inducing a parallel decrease in the number of BrdU cells in the OB and increase in the SVZ, which suggests an impaired migration. In the PFC and ST, 8-OH-DPAT and R0600,175 increase gliogenesis (NG2-labeled cells). This study provides new insights on the serotonergic regulation of critical phases of neurogenesis helpful to understand the neurogenic and gliogenic effects of antidepressant treatments in different brain regions.