Abstract
Although the prefrontal cortex and basal ganglia are functionally interconnected by parallel loops, cellular substrates underlying their interaction remain poorly understood. One novel approach for addressing this issue is microfluidics, a methodology which recapitulates several intrinsic and synaptic properties of cortico-subcortical networks. We developed a microfluidic device where cortical neurons projected onto striatal neurons in a separate compartment. We exploited real-time (low-resolution/high-output) calcium imaging to register network dynamics and characterize the response to glutamatergic and dopaminergic agents. Reconstructed cortico-striatal networks revealed the progressive appearance of cortical VGLUT1 clusters on striatal dendrites, correlating with the emergence of spontaneous and synchronous glutamatergic responses of striatal neurons to concurrent cortical stimulation. Striatal exposure to the NMDA receptor GluN2A subunit antagonist TCN201 did not affect network rhythm, whereas the GluN2B subunit antagonist RO256981 significantly decreased striatal activity. Dopamine application or the D2/D3 receptor agonist, quinpirole, decreased cortico-striatal synchrony whereas the D1 receptor agonist, SKF38393, was ineffective. These data show that cortico-striatal networks reconstructed in a microfluidic environment are synchronized and present characteristics close to those of their in situ counterparts. They should prove instructive for deciphering the molecular substrates of CNS disorders and evaluating the actions of novel therapeutic agents.
Highlights
The basal ganglia loop is a group of subcortical nuclei comprising the striatum, nucleus accumbens, internal and external globus pallidus, substantia nigra and thalamic nuclei
It is believed that DA exerts opposite effects on these neurons, and on network dynamics: whereas D2R activation in iMSNs modifies the up-state transition and diminishes up-state spiking, exactly the opposite effect is observed after dMSN D1R activation[8,9]
VGLUT1 was chosen as a presynaptic reporter of cortical pyramidal neurons because it is absent in GABAergic striatal neurons[3]
Summary
The basal ganglia loop is a group of subcortical nuclei comprising the striatum (caudate nucleus, putamen), nucleus accumbens, internal and external globus pallidus, substantia nigra and thalamic nuclei. D1-like receptors (D1R & D5R) stimulate Gs and Golf proteins leading to recruitment of adenylyl-cyclase, increases in levels of cAMP and activation of PKA This kinase has a wide range of cellular targets, including voltage-gated ion channels and synaptic populations of glutamatergic and other classes of receptor. The balance between DA and glutamate activity is critical for the control of cortico-striatal rhythms, and its disruption can lead to motor deficits and/or cognitive dysfunctions These observations raise the question of the influence of distinct classes of DA receptors on synchrony and oscillatory activity. To devise statistically robust methods for evaluating the network dynamics through low-resolution/high-output calcium imaging, allowing analyses of neuronal frequency, rhythms, and synchrony of the reconstructed networks Using this method to characterize the influence of glutamatergic inputs on striatal rhythms. To likewise explore the modulation of cortico-striatal rhythms by dopamine D2/D3 vs D1 receptors
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