Heterosynaptic Regulation of External Globus Pallidus Inputs to the Subthalamic Nucleus by the Motor Cortex

Abstract

SUMMARY The two principal movement-suppressing pathways of the basal ganglia, the so-called hyperdirect and indirect pathways interact within the subthalamic nucleus (STN). An appropriate level and pattern of hyperdirect pathway cortical excitation and indirect pathway external globus pallidus (GPe) inhibition of the STN are critical for normal movement and greatly perturbed in Parkinson’s disease. Here, we demonstrate that motor cortical inputs to the STN heterosynaptically regulate through activation of postsynaptic NMDA receptors the number of functional GABAA receptor-mediated GPe-STN inputs. Thus, a homeostatic mechanism, intrinsic to the STN, balances cortical excitation by adjusting the strength of GPe inhibition. However, following loss of dopamine, excessive cortical activation of STN NMDA receptors triggers GPe-STN inputs to strengthen abnormally, contributing to the emergence of pathological, correlated activity.

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…Finally, a highly important parkinsonismrelated change in spontaneous discharge is the abnormal level of synchrony between neighboring neurons [144,152]. It is not specifically known how changes such as burst discharges, oscillatory discharge, or abnormal synchrony develop in parkinsonism, although altered striatal output to the extrastriatal basal ganglia, changes in collateral inhibition in the external pallidum [156], or changes in the strength and morphology of synapses within the subthalamopallidal network of connections (see below and [157,158]) may contribute to correlated oscillatory activity in the output nuclei of the basal ganglia [152,159,160] .…”

“…For instance, plasticity at glutamatergic synapses has been demonstrated in animal models of parkinsonism and in patients with PD, affecting the corticostriatal, thalamostriatal, and corticosubthalamic pathways [166][167][168][169][170][171][172][173]. Recent studies have suggested additional plasticity of the GABAergic collaterals within the GPe, as well as the pallidosubthalamic projection, the latter perhaps related to heterosynaptic homeostatic modulations, driven by N-methyl-D-aspartate receptor activation at corticosubthalamic synapses [157,158,174]. The fact that many of these changes can be identified in dopamine depletion models strongly suggests that they are a late consequence of dopamine loss, affecting brain areas rich in dopamine (like the striatum), as well as those with little direct dopamine input (e.g., the STN or the thalamus).…”

Do gap junctions regulate synchrony in the Parkinsonian basal ganglia?

“…In a rotenone rat model of PD, Cx43, mainly expressed by astrocytes, was increased in GPe compared to control rats, possibly as a sign of inflammation [Kawasaki et al, 2009]. Many factors might contribute to altered activity in the basal ganglia, among them possibly a loss of neural pacemaking function [Chan et al, 2011] and synaptic changes (e.g., Fan et al [2013], Miguelez et al [2012], Chu et al [2015]). Since gap junctions show fast functional changes dependent on, for example, neurotransmitter concentrations, pH, or even activity [Spray et al, 1981, Haas et al, 2011, Li et al, 2013, Palacios-Prado et al, 2013, they also might be ideally suited to take part in inducing pathological activity shifts.…”

“…Many of them assume or report a difference in connectivity within the basal ganglia (e. g., Terman et al [2002], Miguelez et al [2012], Fan et al [2013], Gittis et al [2011]) or from cortex to the basal ganglia [Magill et al, 2001, Deffains and Bergman, 2015, Mathai et al, 2015, DeLong and Wichmann, 2015, Chu et al, 2015. It is unclear what connectivity changes are pathological, adaptive, maladaptive or epiphenomenological, and which connectivity changes occur only in animal models but not in patients.…”

“…Nevertheless, the origins of such synchrony and low-frequency oscillations, which have been suggested to underlie motor deficiencies, remain debated (for review, see Galvan et al [2015]). Many studies highlight contributions of motor cortex [Magill et al, 2001, Tachibana et al, 2011, Chu et al, 2015 or the system of the external part of the globus pallidus (GPe) and subthalamic nucleus (STN) for the generation of synchrony and oscillations [Plenz and Kital, 1999, Tachibana et al, 2011. Recently, also other feedback loops have been acknowledged, for example between GPe and striatum , Fujiyama et al, 2015.…”