Glutamatergic Synapses: Molecular Organisation

Siddoway, Benjamin; Hou, Hailong; Xia, Houhui

doi:10.1002/9780470015902.a0000235.pub2

Cited by 6 publications

(5 citation statements)

References 35 publications

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“…However, no direct test has validated this. Moreover, I-2, PP1, and neurabin all localize to excitatory synapses [22, 23], suggesting that they could act together in regulating synaptic transmission.…”

Section: Introductionmentioning

confidence: 99%

PP1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission

Foley

Altimimi

Hou

et al. 2022

Preprint

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Inhibitor-2 (I-2) is a prototypic inhibitor of protein phosphatase-1 (PP1), a major serine-threonine phosphatase that regulates synaptic plasticity and learning and memory. Although I-2 is a potent inhibitor of PP1 in vitro, our previous work has elucidated that, in vivo, I-2 may act as a positive regulator of PP1. Here we show that I-2 and PP1γ, but not PP1α, positively regulate synaptic transmission in hippocampal neurons. Moreover, we demonstrated that I-2 enhances PP1γ interaction with its major synaptic scaffold, neurabin, by Forster resonance energy transfer (FRET)/Fluorescence lifetime imaging microscopy (FLIM) studies, while having a limited effect on PP1 autoinhibitory phosphorylation. Furthermore, our study indicates that the effect of I-2 on PP1 activity in vivo is dictated by I-2 threonine-72 phosphorylation. Our work thus demonstrates a molecular mechanism by which I-2 positively regulates PP1 function in synaptic transmission.

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Section: Introductionmentioning

confidence: 99%

PP1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission

Foley

Altimimi

Hou

et al. 2022

Preprint

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“…Electrophysiological studies in arsenic-exposed rodent models have begun to shed light on potential mechanistic underpinnings of the associated cognitive deficits. Rodents exposed to high arsenic concentrations throughout early development and adulthood demonstrate a decrease in synaptic transmission and long-term potentiation (LTP) (Nelson-Mora et al, 2018) in the hippocampus that may be secondary to altered glutamate transport (Siddoway, 2011). Similar changes in synaptic transmission and plasticity have been demonstrated by ex vivo exposure of hippocampal slices to arsenite metabolites (Kruger et al, 2006;Kruger et al, 2007).…”

Section: Introductionmentioning

confidence: 81%

Early low-level developmental arsenic exposure impacts mouse hippocampal synaptic function

Barnett

et al. 2021

Preprint

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Background: Arsenic is a well-established carcinogen known to increase all-cause mortality, but its effects on the central nervous system are less well understood. Recent epidemiological studies suggest that early life exposure to arsenic is associated with learning deficits and behavioral changes, and increased arsenic exposure continues to affect an estimated 200 million individuals worldwide. Previous studies on arsenic exposure and synaptic function have demonstrated a decrease in synaptic transmission and long-term potentiation in adult rodents, but have relied on in vitro or extended exposure in adulthood. Therefore, little is known about the effect of arsenic exposure in development. Objective: Here, we studied the effects of gestational and early developmental arsenic exposure in juvenile mice. Specifically, our objective was to investigate the impact of arsenic exposure on synaptic transmission and plasticity in the hippocampus. Methods: C57BL/6 females were exposed to arsenic (0, 50ppb, 36ppm) in their drinking water two weeks prior to mating and continued to be exposed to arsenic throughout gestation and after parturition. We then performed field recordings in acute hippocampal slices from the juvenile offspring prior to weaning (P17-P23). In this paradigm, the juvenile mice are only exposed to arsenic in utero and via the mothers milk. Results: High (36ppm) and relatively low (50ppb) arsenic exposure both lead to decreased basal synaptic transmission in the hippocampus of juvenile mice. There was a mild decrease in paired-pulse facilitation in juvenile mice exposed to high, but not low, arsenic, suggesting the alterations in synaptic transmission are primarily post-synaptic. Finally, high developmental arsenic exposure led to a significant increase in long-term potentiation. Discussion: These results suggest that indirect, ecologically-relevant arsenic exposure in early development impacts hippocampal synaptic transmission and plasticity that could underlie learning deficits reported in epidemiological studies.

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“…However, no direct test has validated this. Moreover, I-2, PP1, and neurabin all localize to excitatory synapses ( Siddoway and Xia, 2011 ; Foley et al, 2021b ), suggesting that they could act together in regulating synaptic transmission.…”

Section: Introductionmentioning

confidence: 99%

Protein phosphatase-1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission

Foley

Altimimi²,

Hou³

et al. 2022

Front. Synaptic Neurosci.

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Inhibitor-2 (I-2) is a prototypic inhibitor of protein phosphatase-1 (PP1), a major serine-threonine phosphatase that regulates synaptic plasticity and learning and memory. Although I-2 is a potent inhibitor of PP1 in vitro, our previous work has elucidated that, in vivo, I-2 may act as a positive regulator of PP1. Here we show that I-2 and PP1γ, but not PP1α, positively regulate synaptic transmission in hippocampal neurons. Moreover, we demonstrated that I-2 enhanced PP1γ interaction with its major synaptic scaffold, neurabin, by Förster resonance energy transfer (FRET)/Fluorescence lifetime imaging microscopy (FLIM) studies, while having a limited effect on PP1 auto-inhibitory phosphorylation. Furthermore, our study indicates that the effect of I-2 on PP1 activity in vivo is dictated by I-2 threonine-72 phosphorylation. Our work thus demonstrates a molecular mechanism by which I-2 positively regulates PP1 function in synaptic transmission.

show abstract

Glutamatergic Synapses: Molecular Organisation

Cited by 6 publications

References 35 publications

PP1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission

PP1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission

Early low-level developmental arsenic exposure impacts mouse hippocampal synaptic function

Protein phosphatase-1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission

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