Norepinephrine stabilizes translation‐dependent, homosynaptic long‐term potentiation through mechanisms requiring the cAMP sensor Epac, mTOR and MAPK

Maity, Sabyasachi; Chandanathil, Merin; Millis, Richard M.; Connor, Steven A.

doi:10.1111/ejn.14735

Cited by 13 publications

(8 citation statements)

References 45 publications

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“…NE through activation of ARs increases the strength of synaptic transmission at glutamatergic synapses and modifies the synapses via cAMP signals and protein synthesis to increase long-term plasticity occurring over minutes to hours in duration ( Hopkins and Johnston, 1984 ; Dahl and Sarvey, 1989 ; Harley, 1991 ; Bröcher et al., 1992 ; Harley and Sara, 1992 ; Huang and Kandel, 1996 ; Bramham et al., 1997 ; Erickson et al., 1997 ; Katsuki et al., 1997 ; Thomas and Palmiter, 1997a ; Thomas and Palmiter, 1997b ; Thomas and Palmiter, 1997c ; Izumi and Zorumski, 1999 ; Watabe et al., 2000 ; Walling and Harley, 2004 ; Maity et al., 2020 ). As the signals involves cAMP, most previous studies have concluded that the sole AR in mediating NE effects on long-term plasticity have been the β-ARs ( Maity et al., 2015 ; Hansen and Manahan-Vaughan, 2015 ; Nguyen and Gelinas, 2018 ).…”

Section: Long-term Synaptic Plasticitymentioning

confidence: 99%

α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition

Perez

2020

Front. Pharmacol.

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a 1-adrenergic receptors are G-Protein Coupled Receptors that are involved in neurotransmission and regulate the sympathetic nervous system through binding and activating the neurotransmitter, norepinephrine, and the neurohormone, epinephrine. There are three a 1-adrenergic receptor subtypes (a 1A , a 1B , a 1D) that are known to play various roles in neurotransmission and cognition. They are related to two other adrenergic receptor families that also bind norepinephrine and epinephrine, the band a 2-, each with three subtypes (b 1 , b 2 , b 3 , a 2A , a 2B , a 2C). Previous studies assessing the roles of a 1-adrenergic receptors in neurotransmission and cognition have been inconsistent. This was due to the use of poorly-selective ligands and many of these studies were published before the characterization of the cloned receptor subtypes and the subsequent development of animal models. With the availability of more-selective ligands and the development of animal models, a clearer picture of their role in cognition and neurotransmission can be assessed. In this review, we highlight the significant role that the a 1-adrenergic receptor plays in regulating synaptic efficacy, both short and long-term synaptic plasticity, and its regulation of different types of memory. We will also present evidence that the a 1-adrenergic receptors, and particularly the a 1A-adrenergic receptor subtype, are a potentially good target to treat a wide variety of neurological conditions with diminished cognition.

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Section: Long-term Synaptic Plasticitymentioning

confidence: 99%

α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition

Perez

2020

Front. Pharmacol.

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“…Three PSIs, at commonly used concentrations, were tested in this fashion: (1) Cycloheximide (CHX) which blocks protein synthesis by interfering with tRNA translocation during elongation, at a concentration of 100 μg/ml (355 μM), (2) Anisomycin (ANI) which prevents peptide bond formation by inhibiting peptidyl transferase activity, at 25 μM, and (3) Puromycin which acts as an aminoacyl-tRNA analog leading to premature elongation termination, at 1 μM (for references on inhibitors’ mode of action and working concentrations, see: Yarmolinsky and Haba, 1959 ; Ennis and Lubin, 1964 ; Nathans, 1964 ; Wettstein et al, 1964 ; Grollman, 1967 ; Zinck et al, 1995 ; Fonseca et al, 2006 ; Abbas et al, 2009 ; Schneider-Poetsch et al, 2010 ; Villers et al, 2012 ; Abbas, 2013 ; Signer et al, 2014 ; tom Dieck et al, 2015 ; Gawron et al, 2016 ; Nixon-Abell et al, 2016 ; Chang et al, 2017 ; Li and Götz, 2017 ; Liu et al, 2017 ; Scarnati et al, 2018 ; Cioni et al, 2019 ; Heumüller et al, 2019 ; Maity et al, 2020 ). JF635HT labeling was examined 24 hours after exposing rat cortical neurons in primary culture to CPXH and protein synthesis inhibitors or suitable controls (see Materials and Methods for further details).…”

Section: Resultsmentioning

confidence: 99%

Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Cohen

Ziv²,

Ziv

2022

Front. Mol. Neurosci.

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Synaptic integrity and function depend on myriad proteins - labile molecules with finite lifetimes that need to be continually replaced with freshly synthesized copies. Here we describe experiments designed to expose synaptic (and neuronal) properties and functions that are particularly sensitive to disruptions in protein supply, identify proteins lost early upon such disruptions, and uncover potential, yet currently underappreciated failure points. We report here that acute suppressions of protein synthesis are followed within hours by reductions in spontaneous network activity levels, impaired oxidative phosphorylation and mitochondrial function, and, importantly, destabilization and loss of both excitatory and inhibitory postsynaptic specializations. Conversely, gross impairments in presynaptic vesicle recycling occur over longer time scales (days), as does overt cell death. Proteomic analysis identified groups of potentially essential ‘early-lost’ proteins including regulators of synapse stability, proteins related to bioenergetics, fatty acid and lipid metabolism, and, unexpectedly, numerous proteins involved in Alzheimer’s disease pathology and amyloid beta processing. Collectively, these findings point to neuronal excitability, energy supply and synaptic stability as early-occurring failure points under conditions of compromised supply of newly synthesized protein copies.

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“…While the molecular mechanisms through which noradrenergic transmission reducing drugs may achieve antidepressant-like effects are not well understood at this time, one possibility is that they selectively dampen certain intracellular signaling pathways after acting upon alpha and beta-adrenergic G protein-coupled receptors. There is already evidence, for example, that NE modulates the Ras/MAPK, PI3K/Akt, JAK/STAT pathways (Muthalif et al, 1998 ; Yanagawa et al, 2010 ; Guo et al, 2013 ; Maity et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Are Noradrenergic Transmission Reducing Drugs Antidepressants?

Fitzgerald

2021

Front. Behav. Neurosci.

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Major depressive disorder (MDD) remains a significant public health problem worldwide, and revised treatment strategies are therefore urgently needed, including the creation of novel antidepressant compounds or using existing molecular entities in new ways. Etiologic theories of MDD from decades ago have suggested that synaptic deficiencies of monoaminergic neurotransmitters play a causative role in this neuropsychiatric disorder, and that boosting monoamines with drugs such as SSRIs, SNRIs, TCAs, and MAOIs has antidepressant effects and in some individuals can even induce hypomania or mania. While other factors, such as various intracellular molecular pathways and hippocampal neurogenesis, undoubtedly also play a role in MDD, monoaminergic boosting drugs nonetheless have clearly demonstrated antidepressant properties. There is also, however, a body of studies in the preclinical literature suggesting that monoaminergic transmission reducing drugs, including noradrenergic ones, also have antidepressant-like behavioral properties in rodents. Given that there is increasing evidence that the monoamines have u-shaped or Janus-faced dose-response properties, in which a mid-range value is “optimal” in a variety of behavioral and physiological processes, it is plausible that either too much or too little synaptic norepinephrine in key circuits may exacerbate MDD in some individuals. Here we briefly review rodent depression-related behavioral data, focusing on the forced swim test, from three major classes of noradrenergic transmission reducing drugs (alpha2 agonists, beta blockers, alpha1 antagonists), and find much support for the hypothesis that they have antidepressant-like properties. Whether these drugs are antidepressants in human subjects remains to be determined.

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Norepinephrine stabilizes translation‐dependent, homosynaptic long‐term potentiation through mechanisms requiring the cAMP sensor Epac, mTOR and MAPK

Cited by 13 publications

References 45 publications

α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition

α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition

Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Are Noradrenergic Transmission Reducing Drugs Antidepressants?

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