Biomedical subjects

Pierre-Olivier Fernagut

Publications and source records attributed to Pierre-Olivier Fernagut.

12 recordsLinked to original sources

PubMed2026

Age-dependent reorganization of behavioral and striatal function in Cntnap2 knockout mice.

Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and the presence of restricted and repetitive behaviors. While ASD has a neurodevelopmental origin, it remains a lifelong condition, yet little is known about how its behavioral and neural features evolve across adulthood. Here, we investigated behavioral, synaptic, and structural alterations across the transition from early to mature adulthood in Cntnap2 knockout mice, a widely used model of ASD. Using a longitudinal behavioral approach combined with electrophysiological recordings and morphological analysis, we show that KO mice exhibit increased stereotyped and repetitive behaviors and reduced exploratory activity at both ages. However, detailed analysis of behavioral patterns revealed age-dependent differences, with early adult KO mice displaying increased behavioral persistence that later evolved into distinct patterns of behavioral sequences. These behavioral changes were associated with alterations in inhibitory synaptic transmission in the dorsolateral striatum (DLS), including changes in spontaneous inhibitory postsynaptic current (sIPSC) frequency and temporal structure. In parallel, mature adult KO mice showed structural remodeling of spiny projection neurons, characterized by increased distal dendritic arborization and age-dependent organization of dendritic spines. Together, our findings demonstrate that ASD-related alterations are not static but evolve across adulthood, revealing a multi-level reorganization of behavioral, synaptic, and structural features. These results highlight the importance of considering adulthood stages in ASD and provide new insights into the dynamic nature of the condition.

Animals↗

PubMed2006

Direct regulation of adult brain function by the male-specific factor SRY.

The central dogma of mammalian brain sexual differentiation has contended that sex steroids of gonadal origin organize the neural circuits of the developing brain. Recent evidence has begun to challenge this idea and has suggested that, independent of the masculinizing effects of gonadal secretions, XY and XX brain cells have different patterns of gene expression that influence their differentiation and function. We have previously shown that specific differences in gene expression exist between male and female developing brains and that these differences precede the influences of gonadal hormones. Here we demonstrate that the Y chromosome-linked, male-determining gene Sry is specifically expressed in the substantia nigra of the adult male rodent in tyrosine hydroxylase-expressing neurons. Furthermore, using antisense oligodeoxynucleotides, we show that Sry downregulation in the substantia nigra causes a statistically significant decrease in tyrosine hydroxylase expression with no overall effect on neuronal numbers and that this decrease leads to motor deficits in male rats. Our studies suggest that Sry directly affects the biochemical properties of the dopaminergic neurons of the nigrostriatal system and the specific motor behaviors they control. These results demonstrate a direct male-specific effect on the brain by a gene encoded only in the male genome, without any mediation by gonadal hormones.

Animals↗

PubMed2005

Impact of high-frequency stimulation parameters on the pattern of discharge of subthalamic neurons.

In clinical conditions, high-frequency stimulation (HFS) of subthalamic (STN) neurons in Parkinson's disease is empirically applied at > or =100 Hz (130-185 Hz), with pulses of short duration (60-100 micros) and 1- to 3-mA amplitude. Other parameter values produce no effect or aggravate the symptoms. To gain a better understanding of the mechanisms that underlie the therapeutic action of HFS, we have compared the effects of different combinations of parameter values delivered by clinical stimulators on the activity of STN neurons recorded in whole cell patch-clamp configuration in slices. We showed that none of tested combinations of parameters silenced the neurons. Non-therapeutic combinations i.e., low-frequency pulses (10-50 Hz), even at large amplitude or width, further excited the STN neurons with respect to their spontaneous activity. In contrast, combinations in the therapeutic range (80-185 Hz, 90-200 micros, 500-800 microA) replaced the preexisting activity by spikes, time-locked to the stimuli and thus presenting a striking regularity. When increasing pulse width or amplitude in this high-frequency range, the dual effect was still present but the activity generated became more irregular. We propose that during HFS at clinically relevant parameters, STN neurons behave as stable oscillators entirely driven by the stimulation, giving an average stable STN output that overrides spontaneous activity and introduces high-frequency regular spiking in the basal ganglia network.

Action Potentials↗

PubMed2005

In vivo models of multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disorder of unknown etiology clinically characterized by a combination of parkinsonian, pyramidal, and cerebellar signs. Levodopa-unresponsive parkinsonism is present in 80% of MSA cases, and this dominant clinical presentation (MSA-P) is associated with a combined degeneration of the substantia nigra pars compacta and the striatum in anatomically related areas. The limited knowledge of the pathophysiology of MSA and the lack of therapeutic strategies prompted the development of lesion models reproducing striatonigral degeneration, the substrate of levodopa-unresponsive parkinsonism in MSA-P. This method was carried out first in rats with two different stereotaxic strategies using either two neurotoxins ("double toxin-double lesion") or a single neurotoxin ("single toxin-double lesion"). Double-lesioned rat models showed severe motor impairment compared to those with a single nigral or striatal lesion and helped to mimic different stages of the disease. Systemic models were also developed in mice and primates using the nigral toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the striatal toxin 3-nitropropionic (3-NP). In mice, although MPTP reduced the subsequent sensitivity to 3-NP in a sequential lesion, simultaneous nigral and striatal insults were shown to exacerbate striatal damage. MPTP-treated monkeys displayed a significant worsening of parkinsonism and a loss of levodopa-responsiveness after the appearance of hindlimb dystonia and striatal lesion formation induced by subsequent 3-NP intoxication. The different species and intoxication paradigms used will be useful to investigate functional changes in substantia nigra and striatum and to define neuroprotective, neurorestorative, or symptomatic therapeutic strategies.

Animals↗

PubMed2005

Genetic mouse models of parkinsonism: strengths and limitations.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Patients with PD display a combination of motor symptoms including resting tremor, rigidity, bradykinesia, and postural instability that worsen over time. These motor symptoms are related to the progressive loss of dopamine neurons in the substantia nigra pars compacta. PD patients also suffer from nonmotor symptoms that may precede the cardinal motor symptoms and that are likely related to pathology in other brain regions. Traditional toxin models of PD have focused on the nigrostriatal pathway and the loss of dopamine neurons in this region, and these models have been important in our understanding of PD and in the development of symptomatic treatments for the disease. However, they are limited in that they do not reproduce the full pathology and progression seen in PD, thus creating a need for better models. The recent discovery of specific genes causing familial forms of PD has contributed to the development of novel genetic mouse models of PD. This review discusses the validity, benefits, and limitations of these new models.

Animals↗

PubMed2004

Variable effects of chronic subcutaneous administration of rotenone on striatal histology.

When infused in rats, rotenone, a mitochondrial complex I inhibitor, induces alterations that resemble the histological changes of Parkinson's disease, particularly degeneration of the nigrostriatal dopaminergic system. However, the specificity of rotenone effects has been challenged recently. We have re-examined the alterations caused by rotenone in the substantia nigra and the striatum of rats after infusion of rotenone (2 mg/kg per day s.c.) for 21 days. Three patterns of striatal tyrosine-hydroxylase immunoreactivity (TH-IR) were observed: 46% of animals showed no reduction, and 46% of animals showed diffuse reduction in TH-IR, whereas one animal presented a focal loss of TH-IR in the striatum. Confocal microscopy analysis showed that the vesicular monoamine transporter (VMAT2) was decreased in parallel with TH-IR, strongly suggesting a loss of striatal DA nerve terminals in animals with diffuse or central TH-IR loss. However, no significant loss of TH-IR neurons was observed in the substantia nigra. Analysis of NeuN and DARPP-32 immunoreactivity, and Nissl staining, in the striatum showed no striatal neuronal loss in animals with either preserved TH-IR or diffuse TH-IR reduction. However, in the animal with focal TH-IR loss, severe neuronal loss was evident in the center and the periphery of the striatum, together with microglial activation detected by OX-6 and OX-42 staining. Thus, in most cases, chronic subcutaneous infusion of low doses of rotenone does not induce significant striatal neuronal loss, despite TH-IR and VMAT-IR reduction in a subset of animals, supporting the use of rotenone as a model of Parkinson's disease under carefully controlled experimental conditions.

Animals↗

PubMed2004

Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein.

Accumulation of alpha-synuclein in brain is a hallmark of synucleinopathies, neurodegenerative diseases that include Parkinson's disease. Mice overexpressing alpha-synuclein under the Thy-1 promoter (ASO) show abnormal accumulation of alpha-synuclein in cortical and subcortical regions of the brain, including the substantia nigra. We examined the motor deficits in ASO mice with a battery of sensorimotor tests that are sensitive to alterations in the nigrostriatal dopaminergic system. Male wild-type and ASO mice were tested every 2 months for 8 months for motor performance and coordination on a challenging beam, inverted grid, and pole, sensorimotor deficits in an adhesive removal test, spontaneous activity in a cylinder, and gait. Fine motor skills were assessed by the ability to grasp cotton from a bin. ASO mice displayed significant impairments in motor performance and coordination and a reduction in spontaneous activity as early as 2 months of age. Motor performance and coordination impairments became progressively worse with age and sensorimotor deficits appeared at 6 months. Fine motor skills were altered at 4 months and worsened at 8 months. These data indicate that overexpression of alpha-synuclein induced an early and progressive behavioral phenotype that can be detected in multiple tests of sensorimotor function. These behavioral deficits provide a useful way to assess novel drug therapy in genetic models of synucleinopathies.

Animals↗

PubMed2004

Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone.

Mitochondrial toxins such as the complex 1 inhibitor rotenone are widely used as pesticides and may be present in military environments. Administration of rotenone can induce biochemical and histological alterations similar to those of Parkinson's disease in rats. However, only a subset of animals show these effects and it is unclear whether more subtle alterations are caused by chronic administration of rotenone in those animals that appear resistant to its toxic effects on dopaminergic nerve terminals. To address this question, vehicle or rotenone (2.0, 2.5, or 3.5 mg/kg/day) was administered intravenously or subcutaneously for 21 days to adult rats, and rotenone effects on survival, motor behavior, and striatal tyrosine hydroxylase immunoreactivity (TH-IR) were examined. Both intravenous and subcutaneous rotenone induced a dose-dependent decrease in survival rates. Surviving animals showed a decrease in spontaneous rearing. Locomotor activity and movement initiation time were also altered in some of the experimental groups. Confirming previous results, TH-IR in the striatum was markedly decreased in rats that fell ill early in the study and in a few of the surviving rats with high rotenone doses. However, none of the surviving rats receiving 2.0 mg/kg/day showed TH-IR loss reminiscent of Parkinson's disease, and loss of striatal TH-IR across doses was not correlated with motor behavior in individual rats. Thus, chronic administration of low doses of rotenone induces motor anomalies even in animals that do not develop histological signs of Parkinson's disease, indicating a pervasive neurological effect of moderate mitochondrial dysfunction in vivo.

Animals↗

PubMed2004

Experimental basis for the putative role of GluR6/kainate glutamate receptor subunit in Huntington's disease natural history.

Age of onset of Huntington's disease (HD) statistically correlates with the length of expanded CAG repeats in the IT15 gene. However, other factors such as polymorphism in the 3' untranslated region of the GluR6 kainate receptor gene subunit may contribute to variability in the age at onset. To investigate this issue, we studied the motor disorder and related striatal damage induced by 3-nitropropionic acid (3-NP) subacute administration in GluR6 knockout mice (GluR6(-/-)) as compared to wild-type mice. In two different age groups (6 months and 1 year), we observed that GluR6(-/-) mice did not display more motor impairment nor more striatal histopathological damage than GluR6(+/+) mice, although 1-year-old GluR6(-/-) mice displayed reduced activity parameters either at baseline or after 3-NP administration compared to GluR6(+/+). In both age groups, GluR6(-/-) mice died earlier and displayed earlier motor symptoms during 3-NP-induced metabolic compromise, suggesting that GluR6-containing kainate receptors may be implicated during neurodegeneration, such as in HD, rather than in the final outcome.

Age of Onset↗

PubMed2004

Alpha-synuclein and transgenic mouse models.

Identified as the cause of some familial forms of Parkinson disease (PD) and as one of the major component of Lewy bodies, alpha-synuclein (alpha-syn) became the molecular hallmark of several neurodegenerative conditions now designated as synucleinopathies. Transgenic models have been generated to elucidate its physiological and pathologic roles. Although none of the lines created display dopaminergic neuronal death in the substantia nigra, the models recapitulate some features of synucleinopathies and are useful to study the potential pathogenic role of alpha-synuclein and its molecular partners. This review describes the different alpha-synuclein transgenic models, their clinical relevance to synucleinopathies, and their further utilization to understand the disease process.

Animals↗

PubMed2004

Deleterious effects of minocycline in animal models of Parkinson's disease and Huntington's disease.

Minocycline has been shown to exert anti-inflammatory effects underlying its putative neuroprotective properties in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease and in the R6/2 mouse model of Huntington's disease (HD). However, contradictory results have recently been reported. We report deleterious effects of minocycline in two phenotypic (toxic) models of Parkinson's disease and HD in monkey and mouse. Of seven MPTP-intoxicated female cynomolgus monkeys (0.2 mg/kg, i.v. until day 15), three received minocycline (200 mg b.i.d.). While placebo-MPTP-treated animals displayed mild parkinsonism at day 15, the minocycline/MPTP-treated animals tended to be more affected (P = 0.057) and showed a greater loss of putaminal dopaminergic nerve endings (P < 0.0001). In the 3-nitropropionic acid (3-NP) mouse model of HD, minocycline (45 mg/kg i.p.) was administered 30 min before each i.p. injection of 3-NP (b.i.d., cumulated dose, 360 mg/kg in 5 days). Mice receiving minocycline exhibited a worsening of the mean motor score with a slower recovery slope, more impaired general activity and significantly deteriorated performances on the rotarod, pole test and beam-traversing tasks. The histopathological outcome demonstrated that minocycline-treated mice presented significantly more severe neuronal cell loss in the dorsal striatum. The effect of minocycline vs. 3-NP was also investigated on hippocampal and cortical cell cultures. minocycline blocked 3-NP-induced neurotoxicity at certain doses (1 mm cortical neurons) but not at higher doses (10 mm). Thus, minocycline may have variable and even deleterious effects in different species and models according to the mode of administration and dose.

Animals↗

PubMed2003

Neuropathological and behavioral changes induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of striatonigral degeneration (multiple system atrophy).

We characterized two models of dual nigral and striatal lesions replicating the lesion pattern of striatonigral degeneration, the neuropathological hallmark of parkinsonism associated with multiple system atrophy (SND/MSA-P). For this purpose, we used systemic administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP) in C57BL mice. One group of animals was first injected with MPTP followed by 3NP (MPTP+3-NP model). In the second group 3-NP was injected first, followed by MPTP (3-NP+MPTP model). The behavioral and neuropathological characteristics of these two models were compared to those observed after single 3-NP or MPTP intoxication. Results showed that, compared to control mice, spontaneous nocturnal locomotor activity was preserved in the MPTP+3-NP model, whereas it was reduced by 27% ( P<0.05) in the 3-NP+MPTP model and in animals treated with either 3-NP (27%, P<0.05) or MPTP (23%, P<0.05) alone. Quantitative histological evaluation based on Nissl staining and DARPP-32 immunohistochemistry revealed that 3-NP alone and 3-NP+MPTP treatment produced a marked (greater than 50%) loss of striatal neurons, whereas MPTP+3-NP treatment attenuated loss of striatal neurons by 43%. Further, loss of tyrosine hydroxylase-positive neurons in substantia nigra pars compacta (SNc) was attenuated after 3-NP+MPTP treatment compared to that observed after MPTP (40% vs 74%, P<0.001) and MPTP+3NP treatment (55% vs 74%, P<0.01). Our results show that MPTP-induced nigral lesions attenuate 3-NP toxicity and, reciprocally, that 3-NP-induced striatal lesions reduce MPTP toxicity. This suggests that complex integrative mechanisms are likely to regulate the vulnerability of the striatum and SNc to cell death in SND/MSA-P.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗