AMPA Receptors as Therapeutic Targets for Neurological Disorders

Lee, Kevin; Goodman, Lucy; Fourie, Chantelle; Schenk, Susan; Leitch, Beulah; Montgomery, Johanna M.

doi:10.1016/bs.apcsb.2015.10.004

Cited by 83 publications

(66 citation statements)

References 400 publications

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“…Thus, pharmacological initiation of palmitoylation‐deficient state may potentially be used for drug addiction. Furthermore, AMPARs have long been identified as suitable drug targets for central nervous system (CNS) disorders, such as epilepsy and autism . Thus, targeting palmitoylation signaling to regulate AMPAR function emerges as a novel therapeutic strategy.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, AMPARs have long been identified as suitable drug targets for central nervous system (CNS) disorders, such as epilepsy and autism. 25,26 Thus, targeting palmitoylation signaling to regulate AMPAR function emerges as a novel therapeutic strategy. However, until now, much less is known about the effect of palmitoylation-deficient state on AMPAR function.…”

Section: Introductionmentioning

confidence: 99%

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De‐palmitoylation by N‐(tert‐Butyl) hydroxylamine inhibits AMPAR‐mediated synaptic transmission via affecting receptor distribution in postsynaptic densities

et al. 2018

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

De‐palmitoylation by N‐(tert‐Butyl) hydroxylamine inhibits AMPAR‐mediated synaptic transmission via affecting receptor distribution in postsynaptic densities

et al. 2018

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“…; Lee et al . ). As a result of its crucial role in brain homeostasis, dysregulation of glutamate is an important component of brain dysfunction both on the synaptic and network level.…”

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confidence: 97%

“…Glutamatergic neurotransmission is abundant in the brain and is involved in most neurocircuits. Glutamate exerts effects at a submillisecond timescale (Diamond and Jahr 1997), governing a plethora of physiological processes ranging from synaptic plasticity to neuronal development and degeneration (Picconi et al 2012;Lee et al 2016). As a result of its crucial role in brain homeostasis, dysregulation of glutamate is an important component of brain dysfunction both on the synaptic and network level.…”

mentioning

confidence: 99%

“…As a result of its crucial role in brain homeostasis, dysregulation of glutamate is an important component of brain dysfunction both on the synaptic and network level. For example, pronounced alterations in glutamatergic synaptic transmission is observed upon repeated consumption of drugs of abuse (L€ uscher and Malenka 2011) while overactivity of the glutamatergic system is critical to the generation and propagation of epileptic seizures (Lee et al 2016). Furthermore, in Parkinson's disease (PD), maladaptive neurocircuitry changes lead to pathological synchronization of activity from the glutamatergic subthalamic nucleus (STN) to the globus pallidus externa (GPe; globus pallidus, GP in rodents).…”

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confidence: 99%

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Validated multi‐step approach for in vivo recording and analysis of optogenetically evoked glutamate in the mouse globus pallidus

Viereckel

Konradsson-Geuken

Wallén-Mackenzie

2018

Journal of Neurochemistry

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Precise quantification of extracellular glutamate concentrations upon neuronal activation is crucial for the understanding of brain function and neurological disorders. While optogenetics is an outstanding method for the correlation between distinct neurons and their role in circuitry and behavior, the electrochemically inactive nature of glutamate has proven challenging for recording upon optogenetic stimulations. This difficulty is due to the necessity for using enzyme-coated microelectrodes and the risk for light-induced artifacts. In this study, we establish a method for the combination of in vivo optogenetic stimulation with selective measurement of glutamate concentrations using enzyme-coated multielectrode arrays and amperometry. The glutamatergic subthalamic nucleus (STN), which is the main electrode target site in deep brain stimulation treatment of advanced Parkinson's disease, has recently proven opotogenetically targetable in Pitx2-Cre-transgenic mice and was here used as model system. Upon stereotactic injection of viral Channelrhodopsin2-eYFP constructs into the STN, amperometric recordings were performed at a range of optogenetic stimulation frequencies in the globus pallidus, the main STN target area, in anesthetized mice. Accurate quantification was enabled through a multi-step analysis approach based on self-referencing microelectrodes and repetition of the experimental protocol at two holding potentials, which allowed for the identification, isolation and removal of photoelectric and photoelectrochemical artifacts. This study advances the field of in vivo glutamate detection with combined optogenetics and amperometric recordings by providing a validated analysis framework for application in a wide variety of glutamate-based approaches in neuroscience.

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SAP97‐mediated rescue of NMDA receptor surface distribution in a neuronal model of Huntington's disease

2018

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Huntington's disease (HD) is a genetic neurodegenerative disorder caused by an expansion of the CAG repeat tract in the HTT gene, leading to motor, cognitive, and psychiatric symptoms. At the cellular level, NMDA-type glutamate receptors are upregulated at glutamatergic extrasynaptic sites in HD, triggering cell death signaling pathways and driving HD neurodegeneration. Extrasynaptic and synaptic glutamate receptor trafficking and surface distribution are regulated by the α and β N-terminal isoforms of SAP97, a postsynaptic density protein localized at glutamatergic synapses. Here we examined the surface distribution of NMDARs and AMPARs in a cellular model of HD, and whether the manipulation of individual SAP97 isoforms can regulate receptor distribution in diseased neurons. Using dSTORM super-resolution imaging, we reveal that mutant HTT drives the elevation of extrasynaptic NMDAR clusters located 100-500 nm from the postsynaptic density. This was accompanied by a decline in synaptic NMDAR-mediated currents while surface NMDAR-mediated currents remained unchanged. These effects were induced within 3 days of mutant HTT expression in rat hippocampal neurons in vitro, and were specific for NMDARs and not observed with AMPARs. Intriguingly, upregulation of either α- or βSAP97 expression increased synaptic and/or perisynaptic NMDAR localization and prevented the shift of NMDARs to extrasynaptic sites in mutant HTT neurons. This was accompanied by the rescue of normal synaptic NMDAR-mediated currents. Taken together, our high-resolution data reveals plasticity in surface NMDAR localization driven by mutant HTT and identifies the similar but independent roles of SAP97 N-terminal isoforms in maintaining normal synaptic function in pathological states.

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AMPA Receptors as Therapeutic Targets for Neurological Disorders

Cited by 83 publications

References 400 publications

De‐palmitoylation by N‐(tert‐Butyl) hydroxylamine inhibits AMPAR‐mediated synaptic transmission via affecting receptor distribution in postsynaptic densities

De‐palmitoylation by N‐(tert‐Butyl) hydroxylamine inhibits AMPAR‐mediated synaptic transmission via affecting receptor distribution in postsynaptic densities

Validated multi‐step approach for in vivo recording and analysis of optogenetically evoked glutamate in the mouse globus pallidus

SAP97‐mediated rescue of NMDA receptor surface distribution in a neuronal model of Huntington's disease

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