Changes to interneuron-driven striatal microcircuits in a rat model of Parkinson's disease
Introduction
Medium-sized spiny projection neurons (MSNs) are the most abundant neurons in the rodent striatum, comprising at least 95% of the total striatal neurons. They form two main populations of projection neurons and are the origin of the direct (striatonigral) and the indirect (striatopallidal) pathways connecting the striatum to the basal ganglia (BG) output structures. A heterogeneous group of interneurons makes up the remaining 5% of striatal neurons, which display different electrophysiological, morphological and neurochemical properties. Four main types of striatal interneurons have been described, including the large cholinergic interneurons that express choline acetyltransferase (ChAT+) and that display spontaneous tonic firing, and 3 populations of GABA interneurons: i) fast-spiking neurons positive for the calcium binding protein parvalbumin (PV+); (ii) interneurons of an uncertain electrophysiological signature that express the calcium binding protein calretinin (CR+); and (iii) low-threshold spiking interneurons that contain the neuronal form of nitric oxide synthase (nNOS+), and that also express the peptides somatostatin and neuropeptide Y (Kawaguchi et al., 1995).
Despite their small numbers, interneurons have long been considered to fulfill an essential role in striatal function, mainly due to their expected strategic location at the interface between striatal inputs and outputs, as well as to their unique functional properties. A classic view of BG dysfunction in Parkinson's disease (PD) is founded on the theory of a disruption to the striatal dopamine–acetylcholine balance provoked by a loss of nigral dopamine input and the ensuing cholinergic overactivity, reinforcing the imbalance between the direct and indirect pathways (Duvosin, 1967, Hornykiewicz and Kish, 1987, Pisani et al., 2003). Interest in this theory, and more generally in the role of cholinergic interneurons in movement disorders, was recently renewed (Tepper et al., 2004, Calabresi et al., 2006, Pisani et al., 2007). PV+ fast-spiking neurons also exert powerful influence onto striatal outflow as they mediate a strong and widespread feedforward fast inhibition onto striatal MSNs (Plenz and Kitai, 1998, Tepper et al., 2008). In addition, there is evidence that the activity of these interneurons is not modified after dopamine depletion and that the feedforward inhibition they exert may worsen the imbalance between the indirect and direct pathways (Mallet et al., 2006).
Most of our knowledge on the position of interneurons in striatal circuitry comes from pharmacological and electrophysiological studies. Indeed, information on the anatomical substrates is fragmentary and the possibility that remodeling of synaptic contacts between interneurons and MSNs could contribute to pathological changes in striatal outflow has not been elucidated. By taking advantage of the trans-synaptic spread of the rabies virus (RV), here we provide a global view of the strength of the connections established by the 4 classes of striatal interneurons onto striatonigral and striatopallidal MSNs. These connections have been studied under normal conditions and after removal of the dopamine input following unilateral 6-OHDA delivery in the substantia nigra pars compacta, demonstrating a profound reorganization of the synaptic network involving PV+ and ChAT+ interneurons.
Section snippets
Materials and methods
A total of 20 male Wistar rats with a body weight ranging from 240 to 280 g were used in this study. The animals were handled according to the European Council Directive 86/609/EEC and all the experimental procedures were approved by the Ethical Committee for Animal Testing of the University of Navarra (Ref: 010-06). The experiments requiring the use of RV were carried out in a biosafety level 2 laboratory and all the personnel involved in those experiments had been previously vaccinated. The
Results
The data presented here were gathered from a total of 16 animals since 4 animals were discarded due to mistargeting (n = 2), track labeling (n = 1) or incomplete nigrostriatal lesion (n = 1). As illustrated in Fig. 1, our study finally consisted of 6 animals in which RV was delivered into the GP (3 controls and 3 lesioned animals) and 10 rats in which RV was delivered into the SNr (5 controls and 5 lesioned animals).
Discussion
Here we present an unequivocal anatomical characterization of the neurochemical phenotypes of striatal interneurons that innervate identified striatofugal neurons. In normal conditions, the number of RV-labeled cells within each striatal interneuron population was similar following RV injection into either the GP or the SNr, suggesting that the innervation of the striatopallidal and striatonigral neurons from striatal interneurons is equivalent. However, marked differences were found among the
Acknowledgments
Supported by the Ministerio de Educación y Ciencia (BFU2006-06744), CIBERNED (CB06/05/0006), the Fondo de Investigaciones Sanitarias (PI050137), the Fundación de Investigación Médica Mutua Madrileña, the UTE-project/FIMA, the CNRS (Centre National de la Recherche Scientifique) and Université de la Méditerranée.
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The first two authors participated equally in this work.