Growth hormone rescues hippocampal synaptic function after sleep deprivation

Sleep is required for, and sleep loss impairs, normal hippocampal synaptic N-methyl-d-aspartate (NMDA) glutamate receptor function and expression, hippocampal NMDA receptor-dependent synaptic plasticity, and hippocampal-dependent memory function. Although sleep is essential, the signals linking sleep to hippocampal function are not known. One potential signal is growth hormone. Growth hormone is released during sleep, and its release is suppressed during sleep deprivation. If growth hormone links sleep to hippocampal function, then restoration of growth hormone during sleep deprivation should prevent adverse consequences of sleep loss. To test this hypothesis, we examined rat hippocampus for spontaneous excitatory synaptic currents in CA1 pyramidal neurons, long-term potentiation in area CA1, and NMDA receptor subunit proteins in synaptic membranes. Three days of sleep deprivation caused a significant reduction in NMDA receptor-mediated synaptic currents compared with control treatments. When rats were injected with growth hormone once per day during sleep deprivation, the loss of NMDA receptor-mediated synaptic currents was prevented. Growth hormone injections also prevented the impairment of long-term potentiation that normally follows sleep deprivation. In addition, sleep deprivation led to a selective loss of NMDA receptor 2B (NR2B) from hippocampal synaptic membranes, but normal NR2B expression was restored by growth hormone injection. Our results identify growth hormone as a critical mediator linking sleep to normal synaptic function of the hippocampus.

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Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity

10.1101/2021.08.02.454736 ◽

2021 ◽

Author(s):

Simonas Griesius ◽

Cian O'Donnell ◽

Sophie Waldron ◽

Kerrie L Thomas ◽

Dominic M Dwyer ◽

...

Keyword(s):

Synaptic Plasticity ◽

Nmda Receptor ◽

Potassium Channels ◽

Long Term Potentiation ◽

Autism Spectrum ◽

Synaptic Function ◽

Synaptic Integration ◽

Dendritic Integration ◽

Term Potentiation

Background: Genetic variations indicating loss of function in the DLG2 gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability. DLG2 encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear. Methods: Hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygous Dlg2+/- rat model using ex vivo patch-clamp electrophysiology, pharmacology, and computational modelling. Results: Dlg2+/- rats had increased NMDA receptor-mediated synaptic currents and, conversely, impaired associative long-term potentiation. This impairment resulted from an increase in potassium channel function leading to a decrease in input resistance and reduced supra-linear dendritic integration during induction of associative long-term potentiation. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28- 1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long- term potentiation impairment in the Dlg2+/- rats. Conclusions: Despite increasing synaptic NMDA receptor currents, the combined impact of reduced DLG2 impairs synaptic integration in dendrites resulting in disrupted associative synaptic plasticity. This biological phenotype can be reversed by compound classes used clinically such as muscarinic M1 receptor agonists and is therefore a potential target for therapeutic intervention.

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Defective place cell activity in nociceptin receptor knockout mice with elevated NMDA receptor-dependent long-term potentiation

The Journal of Physiology ◽

10.1113/jphysiol.2004.081802 ◽

2005 ◽

Vol 565 (2) ◽

pp. 579-591 ◽

Cited By ~ 14

Author(s):

Franco A. Taverna ◽

John Georgiou ◽

Robert J. McDonald ◽

Nancy S. Hong ◽

Alexander Kraev ◽

...

Keyword(s):

Nmda Receptor ◽

Knockout Mice ◽

Cell Activity ◽

Long Term Potentiation ◽

Place Cell ◽

Term Potentiation ◽

Nociceptin Receptor

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Rapid eye-movement sleep deprivation does not ‘rescue’ developmentally regulated long-term potentiation in visual cortex of mature rats

Neuroscience Letters ◽

10.1016/s0304-3940(03)00279-9 ◽

2003 ◽

Vol 342 (3) ◽

pp. 196-200 ◽

Cited By ~ 9

Author(s):

James P. Shaffery ◽

Howard P. Roffwarg

Keyword(s):

Visual Cortex ◽

Sleep Deprivation ◽

Eye Movement ◽

Long Term Potentiation ◽

Rapid Eye Movement ◽

Rapid Eye Movement Sleep ◽

Developmentally Regulated ◽

Term Potentiation

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EGFR signaling upregulates surface expression of the GluN2B-containing NMDA receptor and contributes to long-term potentiation in the hippocampus

Neuroscience ◽

10.1016/j.neuroscience.2015.07.021 ◽

2015 ◽

Vol 304 ◽

pp. 109-121 ◽

Cited By ~ 16

Author(s):

Y. Tang ◽

M. Ye ◽

Y. Du ◽

X. Qiu ◽

X. Lv ◽

...

Keyword(s):

Nmda Receptor ◽

Long Term Potentiation ◽

Surface Expression ◽

Egfr Signaling ◽

Term Potentiation

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Photolytic release of nitric oxide modulates NMDA receptor-mediated transmission but does not induce long-term potentiation at hippocampal synapses

Neuropharmacology ◽

10.1016/0028-3908(94)90039-6 ◽

1994 ◽

Vol 33 (11) ◽

pp. 1375-1385 ◽

Cited By ~ 57

Author(s):

K.P.S.J. Murphy ◽

J.H. Williams ◽

N. Bettache ◽

T.V.P. Bliss

Keyword(s):

Nitric Oxide ◽

Nmda Receptor ◽

Long Term Potentiation ◽

Term Potentiation ◽

Hippocampal Synapses

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Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory

Neurobiology of Disease ◽

10.1016/j.nbd.2008.04.011 ◽

2008 ◽

Vol 31 (2) ◽

pp. 250-260 ◽

Cited By ~ 115

Author(s):

Chanel J. Taylor ◽

David R. Ireland ◽

Irene Ballagh ◽

Katie Bourne ◽

Nicola M. Marechal ◽

...

Keyword(s):

Nmda Receptor ◽

Spatial Memory ◽

Amyloid Precursor Protein ◽

Long Term Potentiation ◽

Precursor Protein ◽

Receptor Function ◽

Term Potentiation ◽

Nmda Receptor Function

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Insights into associative long-term potentiation from computational models of NMDA receptor-mediated calcium influx and intracellular calcium concentration changes

Journal of Neurophysiology ◽

10.1152/jn.1990.63.5.1148 ◽

1990 ◽

Vol 63 (5) ◽

pp. 1148-1168 ◽

Cited By ~ 104

Author(s):

W. R. Holmes ◽

W. B. Levy

Keyword(s):

Experimental Data ◽

Nmda Receptor ◽

Nmda Receptors ◽

Dendritic Spine ◽

Long Term Potentiation ◽

Input Frequency ◽

Spine Head ◽

Term Potentiation ◽

Concentration Changes

1. Because induction of associative long-term potentiation (LTP) in the dentate gyrus is thought to depend on Ca2+ influx through channels controlled by N-methyl-D-aspartate (NMDA) receptors, quantitative modeling was performed of synaptically mediated Ca2+ influx as a function of synaptic coactivation. The goal was to determine whether Ca2+ influx through NMDA-receptor channels was, by itself, sufficient to explain associative LTP, including control experiments and the temporal requirements of LTP. 2. Ca2+ influx through NMDA-receptor channels was modeled at a synapse on a dendritic spine of a reconstructed hippocampal dentate granule cell when 1-115 synapses on spines at different dendritic locations were activated eight times at frequencies of 10-800 Hz. The resulting change in [Ca2+] in the spine head was estimated from the Ca2+ influx with the use of a model of a dendritic spine that included Ca2+ buffers, pumps, and diffusion. 3. To use a compelling model of synaptic activation, we developed quantitative descriptions of the NMDA and non-NMDA receptor-mediated conductances consistent with available experimental data. The experimental data reported for NMDA and non-NMDA receptor-channel properties and data from other non-LTP experiments that separated the NMDA and non-NMDA receptor-mediated components of synaptic events proved to be limiting for particular synaptic variables. Relative to the non-NMDA glutamate-type receptors, 1) the unbinding of transmitter from NMDA receptors had to be slow, 2) the transition from the bound NMDA receptor-transmitter complex to the open channel state had to be even slower, and 3) the average number of NMDA-receptor channels at a single activated synapse on a single spine head that were open and conducting at a given moment in time had to be very small (usually less than 1). 4. With the use of these quantitative synaptic conductance descriptions. Ca2+ influx through NMDA-receptor channels at a synapse was computed for a variety of conditions. For a constant number of pulses, Ca2+ influx was calculated as a function of input frequency and the number of coactivated synapses. When few synapses were coactivated, Ca2+ influx was small, even for high-frequency activation. However, with larger numbers of coactivated synapses, there was a steep increase in Ca2+ influx with increasing input frequency because of the voltage-dependent nature of the NMDA receptor-mediated conductance. Nevertheless, total Ca2+ influx was never increased more than fourfold by increasing input frequency or the number of coactivated synapses.(ABSTRACT TRUNCATED AT 400 WORDS)

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