Abstract:

Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2−/− mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson’s disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette’s syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.

Author affiliation: Bello Gay, Estefania Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina

Author affiliation: Casas Cordero, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina

Author affiliation: Galiñanes, Gregorio Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina

Author affiliation: Casey, Eric. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina

Author affiliation: Belluscio, Mariano Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina

Author affiliation: Rodríguez, V. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina

Author affiliation: Noain, Daniela Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina

Author affiliation: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina

Author affiliation: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina

Abstract:

In animal models of Parkinson´s disease cortical oscillations entrain abnormal synchronous rhythms in basal ganglia neurons. A mechanism accounting for these oscillations should: (i) vindicate a key role of the striatum in Parkinson´s disease pathophysiology by considering how alterations in striatal physiology may gate cortico-basal ganglia oscillations; (ii) explain why abnormal basal ganglia oscillations span the whole frequency range of oscillations observed in the normal frontal cortex; and (iii) provide insight into how these oscillations may relate to akinesia. Here we update our proposal that striatal projection neurons (medium spiny neurons) behave as dopamine-dependent filters which normally do not allow the propagation of resting cortical activity through the basal ganglia circuit. After chronic dopamine depletion, cortical oscillations would spread through more excitable medium spiny neurons to entrain the whole indirect pathway. Therefore, akinesia may not be directly related to oscillations, but to the inability of medium spiny neurons to separate salient pieces of cortical information from the ongoing cortical rhythms they are embedded in. We propose that uncontrolled translation of ongoing cortical activity into no-go signals in the indirect pathway induces akinesia. Thus, oscillations would be an extreme manifestation of this excessive permeability of medium spiny neurons to cortical input in advanced stages of Parkinson´s disease.

Author affiliation: Belluscio, Mariano Andres. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Author affiliation: Escande, Mariela Veronica. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Author affiliation: Keifman, Ettel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Author affiliation: Riquelme, Luis Alberto. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Author affiliation: Murer, Mario Gustavo. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Author affiliation: Zold, Camila Lidia. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Abstract:

Developments in microfabrication technology have enabled the production of neural electrode arrays with hundreds of closely-spaced recording sites, and electrodes with thousands of sites are currently under development. These probes will in principle allow the simultaneous recording of very large numbers of neurons. However, use of this technology requires the development of techniques for decoding the spike times of the recorded neurons, from the raw data captured from the probes. There currently exists no practical solution to this problem of ?spike sorting? for large, dense electrode arrays. Here, we present a set of novel tools to solve this problem, implemented in a suite of practical, user-friendly, open-source software. We validate these methods on data from rat cortex, demonstrating error rates as low as 5%.

Author affiliation: Rossant, Cyrille . Colegio Universitario de Londres; Reino Unido

Author affiliation: Kadir, Shabnam N. . Colegio Universitario de Londres; Reino Unido

Author affiliation: Goodman, Dan F. M. . Imperial College London; Reino Unido

Author affiliation: Schulman, John. University Of California Berkeley; Estados Unidos

Author affiliation: Hunter, Maximilian L. D.. Colegio Universitario de Londres; Reino Unido

Author affiliation: Saleem, Aman B.. Colegio Universitario de Londres; Reino Unido

Author affiliation: Grosmark, Andres. University Of New York; Estados Unidos

Author affiliation: Belluscio, Mariano Andres. University Of New York; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina

Author affiliation: Denfield, George H.. Baylor College of Medicine. Department of Neuroscience; Estados Unidos

Author affiliation: Ecker, Alexander S.. Baylor College of Medicine. Department of Neuroscience; Estados Unidos

Author affiliation: Tolias, Andreas S.. Baylor College of Medicine. Department of Neuroscience; Estados Unidos

Author affiliation: Solomon, Samuel. Colegio Universitario de Londres; Reino Unido

Author affiliation: Buzsáki, György . University Of New York; Estados Unidos

Author affiliation: Carandini, Matteo. Colegio Universitario de Londres; Reino Unido

Author affiliation: Harris, Kenneth D.. Colegio Universitario de Londres; Reino Unido