Frequency selectivity and dopamine-dependence of plasticity at glutamatergic synapses in the subthalamic nucleus

Aston Brain Centre, School of Life and Health Sciences, Aston University, Birmingham, UK.
Neuroscience (Impact Factor: 3.36). 12/2011; 203:1-11. DOI: 10.1016/j.neuroscience.2011.12.027
Source: PubMed


In Parkinson's disease, subthalamic nucleus (STN) neurons burst fire with increased periodicity and synchrony. This may entail abnormal release of glutamate, the major source of which in STN is cortical afferents. Indeed, the cortico-subthalamic pathway is implicated in the emergence of excessive oscillations, which are reduced, as are symptoms, by dopamine-replacement therapy or deep brain stimulation (DBS) targeted to STN. Here we hypothesize that glutamatergic synapses in the STN may be differentially modulated by low-frequency stimulation (LFS) and high-frequency stimulation (HFS), the latter mimicking deep brain stimulation. Recordings of evoked and spontaneous excitatory post synaptic currents (EPSCs) were made from STN neurons in brain slices obtained from dopamine-intact and chronically dopamine-depleted adult rats. HFS had no significant effect on evoked (e) EPSC amplitude in dopamine-intact slices (104.4±8.0%) but depressed eEPSCs in dopamine-depleted slices (67.8±6.2%). Conversely, LFS potentiated eEPSCs in dopamine-intact slices (126.4±8.1%) but not in dopamine-depleted slices (106.7±10.0%). Analyses of paired-pulse ratio, coefficient of variation, and spontaneous EPSCs suggest that the depression and potentiation have a presynaptic locus of expression. These results indicate that the synaptic efficacy in dopamine-intact tissue is enhanced by LFS. Furthermore, the synaptic efficacy in dopamine-depleted tissue is depressed by HFS. Therefore the therapeutic effects of DBS in Parkinson's disease appear mediated, in part, by glutamatergic cortico-subthalamic synaptic depression and implicate dopamine-dependent increases in the weight of glutamate synapses, which would facilitate the transfer of pathological oscillations from the cortex.

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    • "It should be pointed out that the experiments reported here were performed in slices obtained from normal rats, and may not represent the effects of STN-HFS and LFS in dopamine depleted preparations. As long-term plasticity mechanisms may be dopamine dependent (Yamawaki et al., 2012; Dupuis et al., 2013), similar measurements from dopamine-depleted slices are further required. HFS is commonly thought to alleviate PD symptoms through inhibiting STN neurons. "
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    ABSTRACT: High frequency stimulation (HFS) of the subthalamic nucleus (STN) is widely used to treat the symptoms of Parkinson's disease (PD) but the mechanism of this therapy is unclear. Using a rat brain slice preparation maintaining the connectivity between the STN and one of its target nuclei, the globus pallidus (GP), we investigated the effects of high and low frequency stimulation (LFS) (HFS 100 Hz, LFS 10 Hz) on activity of single neurons in the STN and GP. Both HFS and LFS caused changes in firing frequency and pattern of subthalamic and pallidal neurons. These changes were of synaptic origin, as they were abolished by glutamate and GABA antagonists. Both HFS and LFS also induced a long-lasting reduction in firing frequency in STN neurons possibly contending a direct causal link between HFS and the outcome DBS. In the GP both HFS and LFS induced either a long-lasting depression, or less frequently, a long-lasting excitation. Thus, in addition to the intrinsic activation of the stimulated neurons, long-lasting stimulation of the STN may trigger prolonged biochemical processes.
    Full-text · Article · Dec 2013 · Frontiers in Systems Neuroscience
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    • "Discussion DBS evokes action potentials in axons located near the stimulation site, thereby activating synapses on efferent fibers (Hashimoto et al., 2003; Lee et al., 2004; McIntyre et al., 2004a; Miocinovic et al., 2006; Moran et al., 2011b; Reese et al., 2011; Windels et al., 2008), but short term depression can limit the rate at which synaptic release results. Our model of DBS-induced short term depression was derived from recordings in rodent SNc and primate GPi during stimulation in STN, but similar evidence of DBS-induced short term depression has been found in several pathways during thalamic (Anderson et al., 2004; Iremonger et al., 2006; Anderson et al., 2006; Middleton et al., 2010), subthalamic (Ammari et al., 2011; Moran et al., 2011b; Shen and Johnson, 2008; Zheng et al., 2011), pallidal (Bugaysen et al., 2011; Erez et al., 2009; McCairn and Turner, 2009), cortical (Yamawaki et al., 2012) and hippocampal (Feng et al., 2013; Kim et al., 2012) stimulation and is believed to arise from a combination of axonal and synaptic failures (Feng et al., 2013; Hanson and Jaeger, 2002; Kim et al., 2012; Zheng et al., 2011). We combined in vitro data, in vivo data and computational modeling to show that this DBS-induced short term depression suppresses the synaptic transfer of firing rate oscillations, synchrony and rate-coded information. "
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    ABSTRACT: High frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used treatment for Parkinson's disease, but its effects on neural activity in basal ganglia circuits are not fully understood. DBS increases the excitation of STN efferents yet decouples STN spiking patterns from the spiking patterns of STN synaptic targets. We propose that this apparent paradox is resolved by recent studies showing an increased rate of axonal and synaptic failures in STN projections during DBS. To investigate this hypothesis, we combine in vitro and in vivo recordings to derive a computational model of axonal and synaptic failure during DBS. Our model shows that these failures induce a short term depression that suppresses the synaptic transfer of firing rate oscillations, synchrony and rate-coded information from STN to its synaptic targets. In particular, our computational model reproduces the widely reported suppression of parkinsonian β oscillations and synchrony during DBS. Our results support the idea that short term depression is a therapeutic mechanism of STN DBS that works as a functional lesion by decoupling the somatic spiking patterns of STN neurons from spiking activity in basal ganglia output nuclei.
    Full-text · Article · Sep 2013 · Neurobiology of Disease
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    ABSTRACT: Abstract Treatment with the classic antipsychotic drugs (APDs), such as haloperidol (HAL), is associated with both acute and chronic motor side effects. Acutely, these drugs may induce extrapyramidal symptoms, whereas a prolonged treatment may result in tardive dyskinesia (TD). Atypical antipsychotics have a lower incidence of motor side effects, which have been partially ascribed to the antagonism of serotonin (5-HT) receptors. Although there is currently no satisfactory pharmacotherapy for TD, deep brain stimulation (DBS) has emerged as a promising therapy. However, the mechanisms underlying its effects remain largely unknown. DBS has been shown to affect several neurotransmitter systems, including 5-HT. In this review, we outline the involvement of 5-HT in the development of HAL-induced catalepsy and TD. We also discuss the evidence for DBS-induced alterations in 5-HT function and the relevance of serotonergic alterations to the antidyskinetic effects of DBS. The evidence suggests that the serotonergic mechanisms may be involved in the acute and chronic motor side effects of APDs as well as in adverse psychiatric effects that have been reported following DBS. However, the current evidence suggests that 5-HT alterations do not play an important role in the effectiveness of DBS in models of dyskinesias induced by chronic APDs.
    No preview · Article · Feb 2013 · Reviews in the neurosciences
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