Dynamics of the Parkinsonian Striatal Microcircuit: Entrainment into a Dominant Network State

Abstract

Neuronal synchronization in basal ganglia circuits plays a key role in the encoding of movement, procedural memory storage and habit formation. Striatal dopamine (DA) depletion during Parkinsonism causes abnormal synchronization in corticobasal ganglia loops resulting in motor dysfunction. However, the dynamics of the striatal microcircuit underlying abnormal synchronization in Parkinsonism is poorly understood. Here we used targeted whole-cell recordings, calcium imaging allowing the recording from dozens of cells simultaneously and analytical approaches, to describe the striking alterations in network dynamics that the striatal microcircuit undergoes following DA depletion in a rat model of Parkinson disease (PD): In addition to a significant enhancement of basal neuronal activity frequent periods of spontaneous synchronization were observed. Multidimensional reduction techniques of vectorized network dynamics revealed that increased synchronization resulted from a dominant network state that absorbed most spontaneously active cells. Abnormal synchronous activity can be virtually abolished by glutamatergic antagonists, while blockade of GABAergic transmission facilitates the engagement of striatal cell assemblies in the dominant state. Finally, a dopaminergic receptor agonist was capable of uncoupling neurons from the dominant state. Abnormal synchronization and "locking" into a dominant state may represent the basic neuronal mechanism that underlies movement disorders at the microcircuit level.

Dopaminergic Modulation of the Striatal Microcircuit: Receptor-Specific Configuration of Cell Assemblies

“…Striatal medium spiny neurons (MSNs) display correlated voltage oscillations in vivo and in vitro (Stern et al, 1997;Vergara et al, 2003;Mahon et al, 2006;Carrillo-Reid et al, 2008;Pomata et al, 2008) that represent distinct behavioral conditions (Mahon et al, 2006;Vautrelle et al, 2009;Yin et al, 2009;Kravitz et al, 2010). Indeed, during pathological situations, MSNs get locked into a dominant network state resembling the lack of movement (Costa et al, 2006;Liang et al, 2008;Jáidar et al, 2010).…”

Comparison of Normal and Parkinsonian Microcircuit Dynamics in the Rodent Striatum

“…The normal dynamics of the microcircuit is gone (Figure). Addition of DA agonists under DA depleted states is capable to modify this state of affairs and partially restore a phase sequence (Jaidar et al, 2010). To conclude, the striatal microcircuit generates phase sequences, activity trajectories, or cycles, that are lost during DA-depletion but that can be partially restored with DA receptor agonists.…”

“…Thus, as a first approach we decided to observe what characteristics of the microcircuit activity are plainly evident in order to establish top-down hypothesis and experimental designs to understand the role of each neuron class during microcircuit activity (Carrillo-Reid et al, 2008). MSNs seldom fire in physiological conditions (without a motor behavior) (Crutcher and DeLong, 1984;Kimura, 1992;Carrillo-Reid et al, 2008;Liang et al, 2008;Vautrelle, 2009;Jaidar et al, 2010), due to their intrinsic inward rectifying K + currents and strong depolarization-activated K + -currents (see above and Bargas et al, 1989;Galarraga et al, 1994;Nisenbaum and Wilson, 1995;Bargas et al, 1999;Tepper et al, 2004). Since MSNs are majority, this characteristic makes the striatum to be classified as a quasi-"silent" nucleus; very different from the neurons of other BG nuclei which exhibit firing all the time (e.g., Nakanishi et al, 1987;Kita and Kitai, 1991;Ibáñez-Sandoval et al, 2007).…”

“…Strikingly, in the striatal parkinsonian microcircuit all active neurons synchronize their bursts with one another (Jaidar et al, 2010). No matter what is the predominant component of an up-state: intrinsic, synaptic or both, the important feature is that up-states work as "windows" for synchronization and correlated activity (Yuste et al, 2005), while action potentials within the up-states need not be synchronized (Wickens and Wilson, 1998).…”

“…And since they were proposed somewhat independently, we have to conclude that biological evidence that put them forward is robust. Imaging technology used in conjunction with targeted recordings will allow the discerning of their operational rules in control and in pathological situations (Cossart et al, 2003;Grinvald et al, 2003;Carrillo-Reid et al, 2008 ;2009a;Jaidar et al, 2010). It perhaps will be possible to record, compare and describe diverse pathological microcircuits.…”