Changes to interneuron-driven striatal microcircuits in a rat model of Parkinson's disease Pascal Salin a, 1 , Iciar P. López b, 1 , Philippe Kachidian a , Pedro Barroso-Chinea b , Alberto J. Rico b , Virginia Gómez-Bautista b , Patrice Coulon c , Lydia Kerkerian-Le Goff a , José L. Lanciego b, ⁎ a Developmental Biology Institute of Marseille-Luminy, UMR 6216 CNRS-Université de la Méditerranée, Marseille, France b Neurosciences Division, Center for Applied Medical Research (CIMA and CIBERNED), University of Navarra Medical College, Pamplona, Spain c Laboratoire de la Plasticité et Physio-Pathologie de la Motricité, UMR 6196 CNRS-Université de la Méditerranée, Marseille, France abstract article info Article history: Received 2 February 2009 Revised 13 March 2009 Accepted 18 March 2009 Available online 31 March 2009 Keywords: Rabies virus ChAT Dopamine Caudate–putamen Basal ganglia Striatal interneurons play key roles in basal ganglia function and related disorders by modulating the activity of striatal projection neurons. Here we have injected rabies virus (RV) into either the rat substantia nigra pars reticulata or the globus pallidus and took advantage of the trans-synaptic spread of RV to unequivocally identify the interneurons connected to striatonigral- or striatopallidal-projecting neurons, respectively. Large numbers of RV-infected parvalbumin (PV+/RV+) and cholinergic (ChAT+/RV+) interneurons were detected in control conditions, and they showed marked changes following intranigral 6-hydroxydopamine injection. The number of ChAT+/RV+ interneurons innervating striatopallidal neurons increased concomitant with a reduction in the number of PV+/RV+ interneurons, while the two interneuron populations connected to striatonigral neurons were clearly reduced. These data provide the first evidence of synaptic reorganization between striatal interneurons and projection neurons, notably a switch of cholinergic innervation onto striatopallidal neurons, which could contribute to imbalanced striatal outflow in parkinsonian state. © 2009 Elsevier Inc. All rights reserved. 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 neuro- chemical properties. Four main types of striatal interneurons have been described, including the large cholinergic interneurons that express choline acetyltransferase (ChAT+) and that display sponta- neous tonic firing, and 3 populations of GABA interneurons: i) fast- spiking neurons positive for the calcium binding protein parvalbu- min (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 interneur- ons 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 stu- dies. Indeed, information on the anatomical substrates is fragmentary Neurobiology of Disease 34 (2009) 545–552 ⁎ Corresponding author. Neuroscience Division, Av Pio XII 55, CIMA, 31008 Pamplona, Spain. Fax: +34 948 194715. E-mail address: jlanciego@unav.es (J.L. Lanciego). 1 The first two authors participated equally in this work. Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2009.03.006 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi