title: Striatopallidal Neuron NMDA Receptors Control Synaptic Connectivity, Locomotor, and Goal-Directed Behaviors.
abstract: The basal ganglia (BG) control action selection, motor programs, habits, and goal-directed learning. The striatum, the principal input structure of BG, is predominantly composed of medium-sized spiny neurons (MSNs). Arising from these spatially intermixed MSNs, two inhibitory outputs form two main efferent pathways, the direct and indirect pathways. Striatonigral MSNs give rise to the activating, direct pathway MSNs and striatopallidal MSNs to the inhibitory, indirect pathway (iMSNs). BG output nuclei integrate information from both pathways to fine-tune motor procedures and to acquire complex habits and skills. Therefore, balanced activity between both pathways is crucial for harmonious functions of the BG. Despite the increase in knowledge concerning the role of glutamate NMDA receptors (NMDA-Rs) in the striatum, understanding of the specific functions of NMDA-R iMSNs is still lacking. For this purpose, we generated a conditional knock-out mouse to address the functions of the NMDA-R in the indirect pathway. At the cellular level, deletion of GluN1 in iMSNs leads to a reduction in the number and strength of the excitatory corticostriatopallidal synapses. The subsequent scaling down in input integration leads to dysfunctional changes in BG output, which is seen as reduced habituation, delay in goal-directed learning, lack of associative behavior, and impairment in action selection or skill learning. The NMDA-R deletion in iMSNs causes a decrease in the synaptic strength of striatopallidal neurons, which in turn might lead to a imbalanced integration between direct and indirect MSN pathways, making mice less sensitive to environmental change. Therefore, their ability to learn and adapt to the environment-based experience was significantly affected.
  
  
  
  The striatum controls habits, locomotion, and goal-directed behaviors by coordinated activation of two antagonistic pathways. Insofar as NMDA receptors (NMDA-Rs) play a key role in synaptic plasticity essential for sustaining these behaviors, we generated a mouse model lacking NMDA-Rs specifically in striatopallidal neurons. To our knowledge, this is the first time that a specific deletion of inhibitory, indirect pathway medium-sized spiny neuron (iMSN) NMDA-Rs has been used to address the role of these receptors in the inhibitory pathway. Importantly, we found that this specific deletion led to a significant reduction in the number and strength of the cortico-iMSN synapses, which resulted in the significant impairments of behaviors orchestrated by the basal ganglia. Our findings indicate that the NMDA-Rs of the indirect pathway are essential for habituation, action selection, and goal-directed learning.
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels B-1070, Belgium, and.
authors.forename: Laurie
authors.initials: L
authors.lastname: Lambot
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels B-1070, Belgium, and.
authors.forename: Elena
authors.initials: E
authors.lastname: Chaves Rodriguez
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels B-1070, Belgium, and.
authors.forename: Delphine
authors.initials: D
authors.lastname: Houtteman
authors.affiliation: Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida 32610.
authors.forename: Yuquing
authors.identifier: 0000-0003-1211-5529
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels B-1070, Belgium, and.
authors.forename: Serge N
authors.initials: SN
authors.lastname: Schiffmann
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels B-1070, Belgium, and.
authors.forename: David
authors.initials: D
authors.lastname: Gall
authors.affiliation: Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels B-1070, Belgium, and adekerch@ulb.ac.be.
authors.forename: Alban
authors.identifier: 0000-0002-0682-5877
authors.initials: A
authors.lastname: de Kerchove d'Exaerde
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003216:Conditioning, Operant / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005917:Globus Pallidus / Q000166:cytology / Q000502:physiology*; D006040:Goals; D006185:Habituation, Psychophysiologic / Q000235:genetics / Q000502:physiology; D008124:Locomotion / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009434:Neural Pathways / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
chemical_list: C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate
keywords: NMDA receptor; goal-directed behavior; spine morphology; striatopallidal neuron; striatum; synaptic transmission