Striatal Lesions Research Articles

Neuropeptide Y mitigates neuropathology and motor deficits in mouse models of Machado-Joseph disease.

Machado-Joseph disease (MJD) is a fatal, dominantly inherited neurodegenerative disorder associated with an expanded polyglutamine tract within the ataxin-3 protein, and characterized by progressive impairment of motor coordination, associated with neurodegeneration of specific brain regions, including cerebellum and striatum. The currently available therapies do not allow modification of disease progression. Neuropeptide Y (NPY) has been shown to exert potent neuroprotective effects by multiple pathways associated with the MJD mechanisms of disease. Thus, we evaluated NPY levels in MJD and investigated whether raising NPY by gene transfer would alleviate neuropathological and behavioural deficits in cerebellar and striatal mouse models of the disease. For that, a cerebellar transgenic and a striatal lentiviral-based models of MJD were used. NPY overexpression in the affected brain regions in these two mouse models was obtained by stereotaxic injection of adeno-associated viral vectors encoding NPY. Up to 8 weeks after viral injection, balance and motor coordination behaviour and neuropathology were analysed. We observed that NPY levels were decreased in two MJD patients' cerebella and in striata and cerebella of disease mouse models. Furthermore, overexpression of NPY alleviated the motor coordination impairments and attenuated the related neuropathological parameters, preserving cerebellar volume and granular layer thickness, reducing striatal lesion and decreasing mutant ataxin-3 aggregation. Additionally, NPY mediated increase of brain-derived neurotrophic factor levels and decreased neuroinflammation markers. Our data suggest that NPY is a potential therapeutic strategy for MJD.

Striatal patch compartment lesions reduce stereotypy following repeated cocaine administration

Stereotypy can be characterized as inflexible, repetitive behaviors that occur following repeated exposure to psychostimulants, such as cocaine (COC). Stereotypy may be related to preferential activation of the patch (striosome) compartment of striatum, as enhanced relative activation of the patch compartment has been shown to positively correlate with the emergence of stereotypy following repeated psychostimulant treatment. However, the specific contribution of the patch compartment to COC-induced stereotypy following repeated exposure is unknown. To elucidate the involvement of the patch compartment to the development of stereotypy following repeated COC exposure, we determined if destruction of this sub-region altered COC-induced behaviors. The neurons of the patch compartment were ablated by bilateral infusion of the neurotoxin dermorphin-saporin (DERM-SAP; 17ng/μl) into the striatum. Animals were allowed to recover for eight days following the infusion, and then were given daily injections of COC (25mg/kg) or saline for one week, followed by a weeklong drug-free period. Animals were then given a challenge dose of saline or COC, observed for 2h in activity chambers and sacrificed. The number of mu-labeled patches in the striatum were reduced by DERM-SAP pretreatment. In COC-treated animals DERM-SAP pretreatment significantly reduced the immobilization and intensity of stereotypy but increased locomotor activity. DERM-SAP pretreatment attenuated COC-induced c-Fos expression in the patch compartment, while enhancing COC-induced c-Fos expression in the matrix compartment. These data indicate that the patch compartment contributes to repetitive behavior and suggests that alterations in activity in the patch vs matrix compartments may underlie to this phenomenon.

Reversible bilateral striatal lesions following Mycoplasma pneumoniae infection associated with elevated levels of interleukins 6 and 8

Reversible bilateral striatal necrosis associated with Mycoplasma pneumoniae (M. pneumoniae) infection is a rare neurological disease. The exact pathogenic mechanism remains unknown. We report reversible bilateral striatal lesions with a favorable outcome secondary to M. pneumoniae infection in an 8-year-old Chinese girl. Cranial MRI showed abnormal signals in bilateral striatum, which disappeared 8 months later. To better understand the pathogenesis of this encephalopathy, we examined cytokines levels in serum and cerebrospinal fluid from this patient. The results revealed the concentrations of interleukin-6 and interleukin-8 increased significantly in serum (26 pg/mL and 66 pg/mL, respectively) and cerebrospinal fluid (122 pg/mL and 325 pg/mL, respectively), and were reduced markedly after the therapy. Intrathecal production of interleukin-6 and interleukin-8 is probably related to the pathogenesis of striatal lesions caused by M. pneumoniae. These cytokines may cause local vascular injury, and finally leading to local vascular occlusion. Our results suggest that interleukin-6 and interleukin-8 may play important roles in the pathogenesis of this disease. This is the first report to describe the role of cytokines in this condition and relevant literature is reviewed. Our findings may lead to better understanding of the pathogenesis of M. pneumoniae-associated striatal lesions.

Lesions of the hippocampus or dorsolateral striatum disrupt distinct aspects of spatial navigation strategies based on proximal and distal information in a cued variant of the Morris water task

The hippocampus and dorsolateral striatum are critically involved in spatial navigation based on extra-maze and intra-maze cues, respectively. Previous reports from our laboratory suggest that behavior in the Morris water task may be guided by both cue types, and rats appear to switch from extra-pool to intra-pool cues to guide navigation in a sequential manner within a given trial. In two experiments, rats with hippocampal or dorsolateral striatal lesions were trained and tested in water task paradigms that involved translation and removal of a cued platform within the pool and translations of the pool itself with respect to the extra-pool cue reference frame. In the first experiment, moment-to-moment analyses of swim behavior indicate that hippocampal lesions disrupt initial trajectories based on extra-pool cues at the beginning of the trial, while dorsolateral striatal lesions disrupt subsequent swim trajectories based on the location of the cued platform at the end of the trial. In the second experiment, lesions of the hippocampus, but not the dorsolateral striatum, impaired directional responding in situations where the pool was shifted within the extra-pool cue array. These results are important for understanding the cooperative interactions between the hippocampus and dorsolateral striatum in spatial learning and memory and establish that these brain areas are continuously involved in goal-directed spatial navigation. These results also highlight the importance of the hippocampus in directional responding in addition to place navigation.

The 6-OHDA mouse model of Parkinson's disease – Terminal striatal lesions provide a superior measure of neuronal loss and replacement than median forebrain bundle lesions

Unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway produce side-biased motor impairments that reflect the motor deficits seen in Parkinson's disease (PD). This toxin-induced model in the rat has been used widely, to evaluate possible therapeutic strategies, but has not been well established in mice. With the advancements in mouse stem cell research we believe the requirement for a mouse model is essential for the therapeutic potential of these and other mouse-derived cells to be efficiently assessed.This aim of this study focused on developing a mouse model of PD using the 129 P2/OLA Hsd mouse strain as this is widely used in the generation of mouse embryonic stem cells. Both unilateral 6-OHDA medial forebrain bundle (MFB) and striatal lesion protocols were compared, with mice analysed for appropriate drug-induced rotational bias. Results demonstrated that lesioned mice responded to d-amphetamine with peak rotation dose at 5mg/kg and 10mg/kg for MFB and striatal lesions respectively. Apomorphine stimulation produced no significant rotational responses, at any dose, in either the MFB or striatal 6-OHDA lesioned mice. Analysis of dopamine neuron loss revealed that the MFB lesion was unreliable with little correlation between dopamine neuron loss and rotational asymmetry. Striatal lesions however were more reliable, with a strong correlation between dopamine neuron loss and rotational asymmetry. Functional recovery of d-amphetamine-induced rotational bias was shown following transplantation of E13 mouse VM tissue into the lesioned striatum; confirming the validity of this mouse model.

Dorsolateral striatal lesions impair navigation based on landmark-goal vectors but facilitate spatial learning based on a "cognitive map".

In three experiments, the nature of the interaction between multiple memory systems in rats solving a variation of a spatial task in the water maze was investigated. Throughout training rats were able to find a submerged platform at a fixed distance and direction from an intramaze landmark by learning a landmark-goal vector. Extramaze cues were also available for standard place learning, or “cognitive mapping,” but these cues were valid only within each session, as the position of the platform moved around the pool between sessions together with the intramaze landmark. Animals could therefore learn the position of the platform by taking the consistent vector from the landmark across sessions or by rapidly encoding the new platform position on each session with reference to the extramaze cues. Excitotoxic lesions of the dorsolateral striatum impaired vector-based learning but facilitated cognitive map-based rapid place learning when the extramaze cues were relatively poor (Experiment 1) but not when they were more salient (Experiments 2 and 3). The way the lesion effects interacted with cue availability is consistent with the idea that the memory systems involved in the current navigation task are functionally cooperative yet associatively competitive in nature.

ADIOL protects against 3-NP-induced neurotoxicity in rats: Possible impact of its anti-oxidant, anti-inflammatory and anti-apoptotic actions.

Huntington's disease (HD) is a progressive neurodegenerative disorder with a wide spectrum of cognitive, behavioral and motor abnormalities. The mitochondrial toxin 3-nitropropionic acid (3-NP) effectively induces specific behavioral changes and selective striatal lesions similar to that observed in HD. Some neurosteroids, synthesized in neurons and glial cells, previously showed neuroprotective abilities. 5-Androstene-3β-17β-diol (ADIOL) is a major metabolite of dehydroepiandrosterone (DHEA) with previously reported anti-inflammatory, anti-apoptotic and neuroprotective activities. The neuroprotective potential of ADIOL in HD was not previously investigated. Therefore, the present study investigated the neuroprotective effects of ADIOL against 3-NP-induced behavioral changes, oxidative stress, inflammation and apoptosis. Intraperitoneal administration of 3-NP (20mg/kg) for 4 consecutive days in rats caused significant loss in body weight, reduced prepulse inhibition (PPI) of acoustic startle response, locomotor hypoactivity with altered cortical/striatal histological structure, increased cortical/striatal oxidative stress, inflammation and apoptosis. Administration of ADIOL (25mg/kg, s.c.) for two days before 3-NP significantly attenuated the reduction in body weights and PPI, increased locomotor activity and restored cortical/striatal histological structure nearly to normal. Moreover, it displayed anti-oxidant, anti-inflammatory and anti-apoptotic activities as evidenced by the elevation of cortical and striatal reduced glutathione levels, reductions of cortical and striatal malondialdehyde, striatal tumor necrosis factor alpha and interleukin-6 levels. Only a small number of iNOS and caspase-3 positive cells were detected in sections from rats pretreated with ADIOL. This study suggests a potential neuroprotective role of ADIOL against 3-NP-induced Huntington's disease-like manifestations. Such neuroprotection can be attributed to its anti-oxidant, anti-inflammatory and anti-apoptotic activities.

Behavioural profile of Wistar rats with unilateral striatal lesion by quinolinic acid (animal model of Huntington disease) post-injection of apomorphine and exposure to static magnetic field.

We analysed the motor behaviour of Wistar rats after 7 days lesion in the left striatum, injected with apomorphine (APO) and stimulated by a continuous magnetic field of 3,200 Gauss. For the behaviour assessment, we utilised the activity cage test and the rotarod test. Sixty-eight male Wistar rats were divided into six groups: control, sham, sham magnetic, lesion, and stimulated South and North Poles. After the experiments, coronal sections of the striatum were taken and stained with Nissl for analysis of the lesion. In the activity cage test for distance (F = 3.19), time of activity (F = 5.46) and crossings (F = 3.31) in all groups, except for the North Pole-stimulated group, we observed a significant increase in these behaviours when compared to the control group. Considering the number of counterclockwise turns, we observed a significant increase in the lesion in the South and North Pole stimulation groups compared with the control group. Highlighting the minor number of counterclockwise turns observed in the North Pole-stimulated group in relation to the South Pole-stimulated and Lesion groups (F = 16.01). The rotarod test revealed a decrease in the time spent in this apparatus for the Lesion group when compared to all other groups (F = 5.46). The morphometric analysis showed a reduction in the number of neurons in the Lesion group in relation to all other groups (F = 5.13). Thus, the results suggest that the static magnetic field north and south promoted a distinct behavioural profile and morphological preservation after 7 days of lesion with quinolinic acid associated with APO.

Multifactorial modulation of susceptibility to l-lysine in an animal model of glutaric aciduria type I

Glutaric aciduria type I is an inherited defect in l-lysine, l-hydroxylysine and l-tryptophan degradation caused by deficiency of glutaryl-CoA dehydrogenase (GCDH). The majority of untreated patients presents with accumulation of neurotoxic metabolites – glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) – and striatal injury. Gcdh−/− mice display elevated levels of GA and 3-OH-GA but do not spontaneously develop striatal lesions. l-lysine-enriched diets (appr. 235mg/d) were suggested to induce a neurological phenotype similar to affected patients. In our hands 93% of mice stressed according to the published protocol remained asymptomatic. To understand the underlying mechanism, we modified their genetic background (F1 C57BL6/Jx129/SvCrl) and increased the daily oral l-lysine supply (235–433mg). We identified three modulating factors, (1) gender, (2) genetic background, and (3) amount of l-lysine. Male mice displayed higher vulnerability and inbreeding for more than two generations as well as elevating l-lysine supply increased the diet-induced mortality rate (up to 89%). Onset of first symptoms leads to strongly reduced intake of food and, thus, l-lysine suggesting a threshold for toxic metabolite production to induce neurological disease. GA and 3-OH-GA tissue concentrations did not correlate with dietary l-lysine supply but differed between symptomatic and asymptomatic mice. Cerebral activities of glyceraldehyde 3-phosphate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and aconitase were decreased. Symptomatic mice did not develop striatal lesions or intracerebral hemorrhages. We found severe spongiosis in the hippocampus of Gcdh−/− mice which was independent of dietary l-lysine supply. In conclusion, the l-lysine-induced pathology in Gcdh−/− mice depends on genetic and dietary parameters.

Hyperglykaemiás hemiballismus: implikációk a hálózatanalízisből a kognitív károsodásra

[Hyperglycaemia induced movement disorders, such as hemiballism are rare disorders. The syndrome is characterised by the triad of hemiballism, contralateral T1-hyperintense striatal lesion and non-ketotic hyperglycaemia. Here we report a patient with untreated diabetes presenting with acute onset of hemiballism. MRI revealed T1 hyperintensity of the head of the caudate nucleus and the anterior putamen. The patient also had acantocytosis. Based on the detailed examination of the neuroradiological results and earlier findings we will imply on the pathomechanism. Based on previous findings microhemorrhages, extensive mineralisation, gemistocytic astrocytosis might play role in the development of the imaging signs. The connectivity pattern of the striatal lesion showed extensive connections to the frontal cortex. In coexistence with that the most severe impairment was found on the phonemic verbal fluency task measuring frontal executive functions. ]

Hyperglykaemiás hemiballismus: implikációk a hálózatanalízisből a kognitív károsodásra

Hyperglycaemia induced movement disorders, such as hemiballism are rare disorders. The syndrome is characterised by the triad of hemiballism, contralateral T1-hyperintense striatal lesion and non-ketotic hyperglycaemia. Here we report a patient with untreated diabetes presenting with acute onset of hemiballism. MRI revealed T1 hyperintensity of the head of the caudate nucleus and the anterior putamen. The patient also had acantocytosis. Based on the detailed examination of the neuroradiological results and earlier findings we will discuss the pathomechanism. Based on previous findings microhemorrhages, extensive mineralisation, gemistocytic astrocytosis might play a role in the development of the imaging signs. The connectivity pattern of the striatal lesion showed extensive connections to the frontal cortex. In coexistence with that the most severe impairment was found on the phonemic verbal fluency task measuring frontal executive functions.

Acute carbon monoxide poisoning and delayed neurological sequelae: a potential neuroprotection bundle therapy

Currently, there is no known optimal therapy for carbon monoxide (CO) poisoning and CO-associated delayed neurological sequelae. Hyperbaric oxygen therapy (HBOT) is a well-known treatment method, but its use for CO poisoning patients is controversial to use due to lack of evidences regarding its efficacy. Thus, it is unlikely that HBOT alone will be accepted as the standard treatment method. In this article, current and potential treatment methods of CO poisoning are presented as well as the tentative multi-factorial pathophysiology. A series of treatments are suggested for use as a bundle therapy, with targeted temperature management as the base treatment method. Such a therapy holds a great potential, especially for the cases where HBOT is not readily available. We suggest further investigations for elucidating the effects of these suggested treatments and their roles in terms of the complex pathophysiology of CO poisoning. Future acceptance of this therapy based on the improved scientific and clinical knowledge may result in injury prevention and minimization of the signs and the symptoms in CO poisoning.

Bilateral Basal Ganglia Lesion after Glufosinate Ammonium (BASTA<sup>®</sup>) Intoxication

Background: Glufosinate ammonium (Basta®) was developed in Japan in 1994 and was introduced to Korea as a non-selective herbicide. Recently, there is increasing concern about the glufosinate ammonium (GLA) intoxication. Case Report: We report a bilateral basal ganglia lesion that developed after Basta® ingestion. Hippocampal cytotoxic edema is usually encountered after GLA intoxication because profound hypotension or prolonged generalized tonic clonic seizures are usually accompanied. However, profound hypotensive episode or elevated creatine kinase was not observed during the hospital admission. After conservative ventilator support and antibiotic care for aspiration pneumonia, the patient was discharged to a chronic care facility. Conclusion: Bilateral striatal lesion except hippocampal involvement is one of the features of GLA intoxication. Toxic properties for GLA and other additives in Basta® should be thoroughly investigated. J Neurocrit Care 2014;7(2):125-128

Exercise training reinstates cortico-cortical sensorimotor functional connectivity following striatal lesioning: development and application of a subregional-level analytic toolbox for perfusion autoradiographs of the rat brain.

Current rodent connectome projects are revealing brain structural connectivity with unprecedented resolution and completeness. How subregional structural connectivity relates to subregional functional interactions is an emerging research topic. We describe a method for standardized, mesoscopic-level data sampling from autoradiographic coronal sections of the rat brain, and for correlation-based analysis and intuitive display of cortico-cortical functional connectivity (FC) on a flattened cortical map. A graphic user interface “Cx-2D” allows for the display of significant correlations of individual regions-of-interest, as well as graph theoretical metrics across the cortex. Cx-2D was tested on an autoradiographic data set of cerebral blood flow (CBF) of rats that had undergone bilateral striatal lesions, followed by 4 weeks of aerobic exercise training or no exercise. Effects of lesioning and exercise on cortico-cortical FC were examined during a locomotor challenge in this rat model of Parkinsonism. Subregional FC analysis revealed a rich functional reorganization of the brain in response to lesioning and exercise that was not apparent in a standard analysis focused on CBF of isolated brain regions. Lesioned rats showed diminished degree centrality of lateral primary motor cortex, as well as neighboring somatosensory cortex—changes that were substantially reversed in lesioned rats following exercise training. Seed analysis revealed that exercise increased positive correlations in motor and somatosensory cortex, with little effect in non-sensorimotor regions such as visual, auditory, and piriform cortex. The current analysis revealed that exercise partially reinstated sensorimotor FC lost following dopaminergic deafferentation. Cx-2D allows for standardized data sampling from images of brain slices, as well as analysis and display of cortico-cortical FC in the rat cerebral cortex with potential applications in a variety of autoradiographic and histologic studies.

The affective modulation of motor awareness in anosognosia for hemiplegia: Behavioural and lesion evidence

The possible role of emotion in anosognosia for hemiplegia (i.e., denial of motor deficits contralateral to a brain lesion), has long been debated between psychodynamic and neurocognitive theories. However, there are only a handful of case studies focussing on this topic, and the precise role of emotion in anosognosia for hemiplegia requires empirical investigation. In the present study, we aimed to investigate how negative and positive emotions influence motor awareness in anosognosia. Positive and negative emotions were induced under carefully-controlled experimental conditions in right-hemisphere stroke patients with anosognosia for hemiplegia (n = 11) and controls with clinically normal awareness (n = 10). Only the negative, emotion induction condition resulted in a significant improvement of motor awareness in anosognosic patients compared to controls; the positive emotion induction did not. Using lesion overlay and voxel-based lesion-symptom mapping approaches, we also investigated the brain lesions associated with the diagnosis of anosognosia, as well as with performance on the experimental task. Anatomical areas that are commonly damaged in AHP included the right-hemisphere motor and sensory cortices, the inferior frontal cortex, and the insula. Additionally, the insula, putamen and anterior periventricular white matter were associated with less awareness change following the negative emotion induction. This study suggests that motor unawareness and the observed lack of negative emotions about one's disabilities cannot be adequately explained by either purely motivational or neurocognitive accounts. Instead, we propose an integrative account in which insular and striatal lesions result in weak interoceptive and motivational signals. These deficits lead to faulty inferences about the self, involving a difficulty to personalise new sensorimotor information, and an abnormal adherence to premorbid beliefs about the body.

Bilateral striatal lesions in a family with mitochondrial 14459G>A mutation

Bilateral striatal lesions in a family with mitochondrial 14459G>A mutation

Melatonin Reduces Projection Neuronal Injury Induced by 3-Nitropropionic Acid in the Rat Striatum

Background: Melatonin has shown a protective effect against various oxidative damages in the nervous system. Our previous studies have also confirmed its effect on behavioral dysfunction of experimental rats and injury of striatal interneurons induced by 3-nitropropionic acid. The present study aimed to further determine the effect of melatonin on the injury of striatal projection neurons induced by 3-nitropropionic acid. Methods: Classic histology, immunohistochemistry, Western blotting and immunoelectron microscopy were applied in this study. Results: The results were as follows: (1) in the striatum, 3-nitropropionic acid induced a clear lesion area with a transition zone around it, in which both D1+ and D2+ fibers were decreased significantly. However, in the group with melatonin treatment, the striatal lesion area was smaller than in the 3-nitropropionic acid group and the loss of D1+ and D2+ fibers was less pronounced than in the 3-nitropropionic acid group. (2) Histochemical results showed that the dendritic spine density of striatal projection neurons was decreased more seriously after 3-nitropropionic acid treatment, whereas the loss of dendritic spines was less marked in the melatonin-treated group than in the 3- nitropropionic acid group. Immunoelectron microscopy showed that the density of D1+ and D2+ dendrites and spines was significantly decreased in the 3-nitropropionic acid group, and the loss of D1+ and D2+ spines as well as D2+ dendrites was significantly reversed by melatonin administration. (3) Western blotting showed that the expression level of projection neuron protein markers decreased more significantly in the 3-nitropropionic acid group than in the control group and increased significantly in the melatonin-treated group. Conclusions: The present results suggest that 3-nitropropionic acid induces serious injury of striatal projection neurons and that melatonin effectively protects against this pathological damage.

AAV.shRNA-mediated downregulation of ROCK2 attenuates degeneration of dopaminergic neurons in toxin-induced models of Parkinson's disease in vitro and in vivo

Parkinson's disease (PD) is a neurodegenerative disorder with prominent neuronal cell death in the substantia nigra (SN) and other parts of the brain. Previous studies in models of traumatic and neurodegenerative CNS disease showed that pharmacological inhibition of Rho-associated kinase (ROCK), a molecule involved in inhibitory signaling in the CNS, by small-molecule inhibitors improves neuronal survival and increases regeneration. Most small-molecule inhibitors, however, offer only limited target specificity and also inhibit other kinases, including both ROCK isoforms. To establish the role of the predominantly brain-expressed ROCK2 isoform in models of regeneration and PD, we used adeno-associated viral vectors (AAV) to specifically knockdown ROCK2 in neurons.Rat primary midbrain neurons (PMN) were transduced with AAV expressing short-hairpin-RNA (shRNA) against ROCK2 and LIM-domain kinase 1 (LIMK1), one of the downstream targets of ROCK2. While knock-down of ROCK2 and LIMK1 both enhanced neurite regeneration in a traumatic scratch lesion model, only ROCK2-shRNA protected PMN against 1-methyl-4-phenylpyridinium (MPP+) toxicity. Moreover, AAV.ROCK2-shRNA increased levels of the pro-survival markers Bcl-2 and phospho-Erk1.In vivo, AAV.ROCK2-shRNA vectors were injected into the ipsilateral SN and a unilateral 6-OHDA striatal lesion was performed. After four weeks, behavioral, immunohistochemical and biochemical alterations were investigated. Downregulation of ROCK2 protected dopaminergic neurons in the SN from 6-OHDA-induced degeneration and resulted in significantly increased TH-positive neuron numbers. This effect, however, was confined to nigral neuronal somata as striatal terminal density, dopamine and metabolite levels were not significantly preserved. Interestingly, motor behavior was improved in the ROCK2-shRNA treated animals compared to control after four weeks.Our studies thus confirm ROCK2 as a promising therapeutic target in models of PD and demonstrate that neuron-specific inhibition of ROCK2 promotes survival of lesioned dopaminergic neurons.

P.1.g.049 Disruption of MEK–ERK activation in brain during midazolam-induced sleep in mice

Excessive activation of non-NMDA receptors, AMPA and kainate, contributes to neuronal degeneration in acute and progressive pathologies, possibly including schizophrenia. Because 5-HT1A receptor agonists have neuroprotective properties (e.g., against NMDA-induced neurotoxicity), we compared the effects of the antipsychotics, clozapine, ziprasidone and aripiprazole, that are partial agonists at 5-HT1A receptor, with those of haloperidol, which is devoid of 5-HT1A agonist properties, on kainic acid (KA)-induced striatal lesion volumes, in C57Bl/6N mice. The involvement of 5-HT1A receptors was determined by antagonist studies with WAY100635, and data were compared with those obtained using the potent and high efficacy 5-HT1A receptor agonist, F13714. Intra-striatal KA lesioning and measurement of lesion volumes using cresyl violet staining were carried out at 48 h after surgery. F13714, antipsychotics or vehicle were administered ip twice, 30 min before and 3 1/2 h after KA injection. WAY100635 (0.63 mg/kg) or vehicle were given sc 30 min before each drug injection. Clozapine (2 × 10 mg/kg), ziprasidone (2 × 20 mg/kg) and aripiprazole (2 × 10 mg/kg) decreased lesion volume by 61%, 59% and 73%, respectively. WAY100635 antagonized the effect of ziprasidone and of aripiprazole but only slightly attenuated that of clozapine. In contrast, haloperidol (2 × 0.16 mg/kg) did not affect KA-induced lesion volume. F13714 dose-dependently decreased lesion volume. The 61% decrease of lesion volume obtained with F13714 (2 × 0.63 mg/kg) was antagonized by WAY100635. WAY100635 alone did not affect lesion volume. These results show that 5-HT1A receptor activation protects against KA-induced striatal lesions and indicate that some atypical antipsychotic agents with 5-HT1A agonist properties may protect against excitotoxic injury, in vivo.

Alpha-synuclein mutations impair axonal regeneration in models of Parkinson's disease.

The dopaminergic (DAergic) nigrostriatal tract has an intrinsic regenerative capacity which can be impaired in Parkinson's disease (PD). Alpha-synuclein (aSyn) is a major pathogenic component in PD but its impact on DAergic axonal regeneration is largely unknown. In this study, we expressed pathogenic variants of human aSyn by means of recombinant adeno-associated viral vectors in experimental paradigms of DAergic regeneration. In a scratch lesion model in vitro, both aSyn(A30P) and aSyn(A53T) significantly reduced DAergic neurite regeneration and induced loss of TH-immunopositive cells while aSyn(WT) showed only minor cellular neurotoxic effects. The striatal density of TH-immunopositive axons in the striatal 6-OHDA lesion mouse model was attenuated only by aSyn(A30P). However, striatal expression levels of the regeneration marker GAP-43 in TH-immunopositive fibers were reduced by both aSyn(A30P) and aSyn(A53T), but not by aSyn(WT), which was associated with an activation of the ROCK signaling pathway. Nigral DAergic cell loss was only mildly enhanced by additional overexpression of aSyn variants. Our findings indicate that mutations of aSyn have a strong impact on the regenerative capacity of DAergic neurons, which may contribute to their pathogenic effects.