Striking the Right Balance: Cortical Modulation of the Subthalamic Nucleus-Globus Pallidus Circuit
Authors: Kevin J. Mastro, Aryn H. Gittis
Journal: Neuron (2015)

The subthalamic nucleus-globus pallidus network is a potential source of oscillations in Parkinson’s disease, but the mechanism is unknown. In this issue of Neuron, Chu et al., 2015Chu H.-Y. Atherton J.F. Wokosin D. Surmeier D.J. Bevan M.D. Neuron. 2015; 85 (this issue): 364-376Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar present a cortically driven form of heterosynaptic plasticity that could promote oscillatory activity after dopamine depletion. The subthalamic nucleus-globus pallidus network is a potential source of oscillations in Parkinson’s disease, but the mechanism is unknown. In this issue of Neuron, Chu et al., 2015Chu H.-Y. Atherton J.F. Wokosin D. Surmeier D.J. Bevan M.D. Neuron. 2015; 85 (this issue): 364-376Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar present a cortically driven form of heterosynaptic plasticity that could promote oscillatory activity after dopamine depletion. Neuronal oscillations can synchronize activity within networks and across brain regions (Buzsáki and Draguhn, 2004Buzsáki G. Draguhn A. Science. 2004; 304: 1926-1929Crossref PubMed Scopus (4127) Google Scholar). Although they are a healthy form of communication in many brain areas, their dysregulation is being increasingly observed in a number of diseases. Abnormal, excessive oscillatory activity in Parkinson’s disease (PD), for example, disrupts information transfer through the cortico-basal ganglia circuit and impairs normal selection or suppression of actions (Brown, 2007Brown P. Curr. Opin. Neurobiol. 2007; 17: 656-664Crossref PubMed Scopus (314) Google Scholar). PD is characterized by the loss of dopamine in the basal ganglia (BG) circuit that leads to devastating motor dysfunction. Symptom progression has been linked to the appearance of highly synchronized oscillatory activity across cortico-basal ganglia regions, particularly in the beta frequency range (15–30 Hz) where the origin and mechanism of action is unknown (Brown, 2007Brown P. Curr. Opin. Neurobiol. 2007; 17: 656-664Crossref PubMed Scopus (314) Google Scholar). Moreover, the current treatments—dopamine replacement and high-frequency deep brain stimulation—target BG nuclei and often disrupt or resolve abnormal beta oscillations, but pathological activity patterns quickly return if treatments are interrupted. The reciprocally connected subthalamic nucleus (STN) and external segment of the globus pallidus (GPe) form a central pacemaker in the BG that has been implicated in the onset, progression, and maintenance of harmful oscillatory activity (Bevan et al., 2002Bevan M.D. Magill P.J. Terman D. Bolam J.P. Wilson C.J. Trends Neurosci. 2002; 25: 525-531Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). In healthy individuals, STN-GPe activity is desynchronized and uncorrelated, and its relationship to voluntary movement is characterized by complex spatiotemporal firing (Wichmann and DeLong, 1996Wichmann T. DeLong M.R. Curr. Opin. Neurobiol. 1996; 6: 751-758Crossref PubMed Scopus (617) Google Scholar). The STN receives monosynaptic cortical excitation, known as the hyperdirect pathway, which has been linked to a rapid, immediate stop signal (Schmidt et al., 2013Schmidt R. Leventhal D.K. Mallet N. Chen F. Berke J.D. Nat. Neurosci. 2013; 16: 1118-1124Crossref PubMed Scopus (257) Google Scholar). The STN also receives indirect cortical information through the GPe, known as the indirect pathway, which is responsible for the suppression or cancellation of motor plans (Sano et al., 2013Sano H. Chiken S. Hikida T. Kobayashi K. Nambu A. J. Neurosci. 2013; 33: 7583-7594Crossref PubMed Scopus (83) Google Scholar). Neurons in the STN must integrate the GABAergic input from the GPe and the glutamatergic input from the cortex to appropriately stop or pause behaviors. Therefore, the balance between cortical excitation and pallidal inhibition are critical for normal function, and perturbations may underlie disease conditions. In idiopathic and experimental PD, the activity of STN-GPe network becomes highly synchronized and rhythmic with the emergence of beta-band frequency activity (Bevan et al., 2002Bevan M.D. Magill P.J. Terman D. Bolam J.P. Wilson C.J. Trends Neurosci. 2002; 25: 525-531Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar). The synaptic mechanisms driving this change in patterning are unknown, but the STN-GPe network is well positioned to produce and propagate harmful oscillations. Computational modeling paired with experimental observations have shown that extensive GPe collaterals, strong but selective reciprocity of the STN-GPe connections, and intrinsic autonomous properties provide the necessary tools to create a strong oscillator (Holgado et al., 2010Holgado A.J. Terry J.R. Bogacz R. J. Neurosci. 2010; 30: 12340-12352Crossref PubMed Scopus (175) Google Scholar, Plenz and Kital, 1999Plenz D. Kital S.T. Nature. 1999; 400: 677-682Crossref PubMed Scopus (541) Google Scholar). In this issue of Neuron, Chu et al. discover that high levels of cortical activity onto STN neurons can induce heterosynaptic long-term potentiation (hLTP) of GPe synapses. Strengthening of GPe inputs to the STN after dopamine depletion has been shown previously (Fan et al., 2012Fan K.Y. Baufreton J. Surmeier D.J. Chan C.S. Bevan M.D. J. Neurosci. 2012; 32: 13718-13728Crossref PubMed Scopus (88) Google Scholar), but the important conceptual advance of the present study is that the potentiation of GPe synapses is mechanistically linked to that of cortical synapses. The authors hypothesize that under normal conditions, hLTP serves an adaptive, homeostatic role to maintain a healthy balance between the hyperdirect and indirect pathway in the STN. However, after dopamine depletion, pathologically elevated cortical input to the STN triggers excessive induction of hLTP at GPe synapses, which becomes maladaptive to circuit function and contributes to or even exacerbates pathological oscillations. Several mechanisms of heterosynaptic plasticity have been described at GABAergic synapses (Castillo et al., 2011Castillo P.E. Chiu C.Q. Carroll R.C. Curr. Opin. Neurobiol. 2011; 21: 328-338Crossref PubMed Scopus (162) Google Scholar). One mechanism in particular, NMDA-dependent release of nitric oxide (NO) to strengthen nearby inhibitory synapses (Nugent et al., 2007Nugent F.S. Penick E.C. Kauer J.A. Nature. 2007; 446: 1086-1090Crossref PubMed Scopus (252) Google Scholar), was of particular interest because STN neurons contain the necessary synthase (nitric oxide synthase [NOS]) while GPe neurons contain the necessary transducers (guanylate cyclase [GC] and protein kinase G [PKG]). To study the mechanisms of heterosynaptic long-term potentiation (hLTP) in slices, Chu et al. transfected the motor cortex (M1) with a channelrhodopsin-containing virus and optically stimulated terminals in the STN. GPe inputs were activated using electrical stimulation through an electrode placed within the internal capsule. Using multiple pharmacological manipulations, the authors demonstrate that presynaptic, NO-dependent plasticity is present at GPe-STN synapses. However, upon further experimentation, the authors found that a presynaptic mechanism was not the only mechanism of hLTP at the synapse. In the presence of a NOS inhibitor, postsynaptic hLTP was rescued by directly activating NMDA receptors. Two approaches were used to uncover the postsynaptic mechanism contributing to hLTP. First, immunohistochemistry revealed an increase in the density of the GABAAR scaffolding protein, gephyrin, as well as an increase in the density of the γ2 subunit of the GABAAR after hLTP induction, consistent with the findings of Fan et al., 2012Fan K.Y. Baufreton J. Surmeier D.J. Chan C.S. Bevan M.D. J. Neurosci. 2012; 32: 13718-13728Crossref PubMed Scopus (88) Google Scholar, in dopamine-depleted tissue. Second, uncaging of RuBi-GABA produced larger inhibitory responses after hLTP induction compared to baseline, consistent with the increase in the number of GABAAR observed immunohistochemically. These results show for the first time that hLTP has both a presynaptic (NO-GC-PKG signal cascade) and postsynaptic (SNARE-dependent insertion of GABAARs) mechanism at the same synapse (Figure 1). To determine whether hLTP is present in vivo, the authors used a viral strategy to knock down expression of the GluN1 subunit, and hence NMDARs, in a portion of STN neurons; if hLTP is normally engaged in vivo, the strength of inhibitory inputs should be decreased onto neurons lacking NMDARs. Comparisons of the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) recorded from infected and uninfected neurons showed that inhibitory inputs were indeed weakened onto neurons lacking NMDARs in both control and dopamine-depleted slices. These results confirmed that NMDAR activity can modulate the strength of GPe-STN inputs under both control and dopamine-depleted conditions. If the strengthening of GPe-STN synapses via hLTP acts in a homeostatic manner, then it should help to preserve a constant ratio between excitation and inhibition. This prediction was tested under control conditions, where the authors measured the ratio of excitatory and inhibitory synaptic inputs both pre- and post-induction of hLTP. In support of a homeostatic function, the ratio of excitation and inhibition remained constant. The fact that hLTP is regulated by the degree of activity of cortical inputs to the STN suggests that the excessive cortical patterning that occurs after dopamine loss could drive hLTP at GPe-STN synapses to maximal capacity. To test this idea, the authors attempted to induce hLTP in acute slices prepared from dopamine-depleted mice, but found that it was occluded. This occlusion experiment implies that hLTP is maximally engaged at all GPe-STN synapses after dopamine depletion. However, the results of the viral knockdown experiment showed that hLTP was also present at some synapses under control conditions, so there may be other factors contributing to hLTP occlusion after dopamine depletion. One possibility is that hLTP ceases to be homeostatic under dopamine-depleted conditions, but the ratio between excitatory and inhibitory inputs was not examined in dopamine-depleted mice, so this remains an open question. How might hLTP contribute to pathological oscillations in the Parkinsonian brain? We know from in vivo studies of PD patients and animal models that cortical excitation becomes more synchronous and out of phase to pallidal inhibition (Goldberg et al., 2002Goldberg J.A. Boraud T. Maraton S. Haber S.N. Vaadia E. Bergman H. J. Neurosci. 2002; 22: 4639-4653PubMed Google Scholar, Mallet et al., 2008Mallet N. Pogosyan A. Márton L.F. Bolam J.P. Brown P. Magill P.J. J. Neurosci. 2008; 28: 14245-14258Crossref PubMed Scopus (292) Google Scholar). This may be the force necessary to activate NMDA-dependent plasticity and drive the strengthening of GPe-STN synapses. This increase in GPe synaptic strength could then further promote pathological activity by deinactivation of Nav channels (Baufreton et al., 2005Baufreton J. Atherton J.F. Surmeier D.J. Bevan M.D. J. Neurosci. 2005; 25: 8505-8517Crossref PubMed Scopus (121) Google Scholar). Therefore, inducing hLTP in the STN-GPe network that contains an intrinsic propensity for oscillations (STN excites GPe, GPe inhibits STN) would not only be able to mimic the beta-band oscillations but also propagate them to multiple brain regions. Interestingly, a patient with PD must experience profound dopamine loss before the onset of motor dysfunction. The hLTP mechanism presented here fits well into how this may occur. An individual will experience a gradual loss of dopamine, which results in changes in firing rate and pattern of GPe and cortical inputs and therefore engages hLTP. The STN may be able to balance the changing landscape of basal ganglia firing and pattern for a period of time but eventually is unable to overcome the loss of an important neuromodulator and other anatomical and physiological changes in connected brain regions. There then comes a point where the synaptic mechanism switches from adaptive to maladaptive. Dopamine replacement therapy can restore some functionality to the circuit, but if synaptic mechanisms such as hLTP are not reversed, circuit dysfunction will persist until solutions are found to restore synaptic connections to healthy states. Heterosynaptic Regulation of External Globus Pallidus Inputs to the Subthalamic Nucleus by the Motor CortexChu et al.NeuronJanuary 8, 2015In BriefChu et al. show that glutamatergic corticosubthalamic transmission heterosynaptically regulates the strength of GABAergic pallidosubthalamic inhibition. Under normal conditions, this mechanism homeostatically balances synaptic excitation and inhibition. However, in experimental Parkinson’s disease, heterosynaptic regulation drives pathological strengthening of pallidosubthalamic inputs. Full-Text PDF Open Archive