Impact of the lesion procedure on the profiles of motor impairment and molecular responsiveness to L-DOPA in the 6-hydroxydopamine mouse model of Parkinson's disease

Abstract

6-Hydroxydopamine (6-OHDA) lesions are being used in the mouse for basic research on Parkinson's disease and L-DOPA-induced dyskinesia. We set out to compare unilateral lesion models produced by intrastriatal or intramesencephalic injections of a fixed 6-OHDA concentration (3.2 μg/μl) in C57BL/6 mice. In the first experiment, toxin injections were performed either at two striatal coordinates (1 or 2 μl per site, termed "striatum(2 × 1 μl)" and "striatum(2 × 2 μl)" models), in the medial forebrain bundle (MFB), or in the substantia nigra pars compacta (SN) (1 μl per site). All the four lesion models produced significant forelimb use asymmetry, but spontaneous turning asymmetry only occurred in the MFB and striatum(2 × 2 μl) models. After the behavioral studies, the induction of phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) by acute L-DOPA (30 mg/kg) was used as a marker of post-synaptic supersensitivity. Striatal pERK1/2 expression was sparse in the SN and striatum(2 × 1 μl) groups, but pronounced in the striatum(2 × 2 μl) and MFB-lesioned mice. In further experiments, mice with MFB and striatal(2 × 2 μl) lesions were used to compare behavioral and molecular responses to chronic L-DOPA treatment (12 days at 3 and 6 mg/kg/day). Maximally severe abnormal involuntary movements (AIMs) occurred in all MFB-lesioned mice, whereas only 35% of the mice with striatal lesions developed dyskinesia. Striatal tissue levels of dopamine were significantly lower in the dyskinetic animals (both MFB and striatum(2 × 2 μl) groups) in comparison with the non-dyskinetic ones. Noradrenaline levels were significantly reduced only in MFB lesioned animals and did not differ among the dyskinetic and non-dyskinetic cases with striatal lesions. In all groups, the L-DOPA-induced AIM scores correlated closely with the number of cells immunoreactive for tyrosine hydroxylase or FosB/∆FosB in the striatum. In conclusion, among the four lesion procedures examined here, only the MFB and striatum(2 × 2 μl) models yielded a degree of dopamine denervation sufficient to produce spontaneous postural asymmetry and molecular supersensitivity to L-DOPA. Both lesion models are suitable to reproduce L-DOPA-induced dyskinesia, although only MFB lesions yield a pronounced and widespread expression of post-synaptic supersensitivity markers in the striatum.

Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy

“…The dyskinesia-enhancing effect of dSPN stimulation was clear-cut on all types of involuntary movements, i.e., axial, limb, and orofacial AIMs (see color-coded specification of AIM subtypes in Figure 5, bar diagram). The dose of 3 mg/kg L-DOPA is typically used to induce LID in this animal model (25,29). As expected, this L-DOPA dosage elicited moderate to severe dyskinesia in both genotypes (cf.…”

“…We next applied the same chemogenetic approach to a unilateral mouse model of parkinsonism that is widely used for studies of striatal signaling and plasticity (22)(23)(24)(25)(26)(27)(28)(29). BAC-transgenic mice sustained 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal DA pathway on one side of the brain, and AAV-DIO-hM3Dq was injected into the DA-denervated striatum 3 weeks later.…”

“…Three topographic subtypes of AIMs (axial, limb, orolingual, or orofacial) were rated every 20th minute during 180 minutes following drug injection (25,68). Unless otherwise specified, AIM values reported in all figures are the sum of axial, limb, and orofacial scores.…”

Levodopa-Induced Dyskinesia Is Strongly Associated with Resonant Cortical Oscillations

“…The extent of the lesions was confirmed by TH immunohistochemistry as described in previous studies (Francardo et al, 2011). Briefly, the sections were washed three times in 0.02 M potassium PBS (KPBS) to rinse away the antifreeze.…”

GαolfMutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia

“…G␣ olf /cAMP/PKA hypersensitivity does not account for the strong activation of ERK by L-DOPA in dyskinetic animals In animal models of PD, a strong ERK activation in response to L-DOPA is observed, correlated with the occurrence of LID (Gerfen et al, 2002;Pavó n et al, 2006;Santini et al, 2007Santini et al, , 2009bSantini et al, , 2010Westin et al, 2007;Nicholas et al, 2008;Fasano et al, 2010;Francardo et al, 2011). ERK activation occurs in D 1 R-expressing striatonigral neurons (Gerfen et al, 2002;Santini et al, 2009b) and after prolonged treatment in cholinergic interneurons (Ding et al, 2011).…”