scholarly journals BACE1 controls synaptic function through modulating release of synaptic vesicles

2021 ◽  
Author(s):  
Brati Das ◽  
Neeraj Singh ◽  
Annie Y. Yao ◽  
John Zhou ◽  
Wanxia He ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Amyloid Peptides ◽  
Cognitive Behaviors ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Severe Reduction ◽  
Metabotropic Glutamate Receptor 1

AbstractBACE1 initiates production of β-amyloid peptides (Aβ), which is associated with cognitive dysfunction in Alzheimer’s disease (AD) due to abnormal oligomerization and aggregation. While BACE1 inhibitors show strong reduction in Aβ deposition, they fail to improve cognitive function in patients, largely due to its role in synaptic function. We show that BACE1 is required for optimal release of synaptic vesicles. BACE1 deficiency or inhibition decreases synaptic vesicle docking in the synaptic active zones. Consistently, BACE1-null mice or mice treated with clinically tested BACE1 inhibitors Verubecestat and Lanabecestat exhibit severe reduction in hippocampal LTP and learning behaviors. To counterbalance this synaptic deficit, we discovered that BACE1-null mice treated with positive allosteric modulators (PAMs) of metabotropic glutamate receptor 1 (mGluR1), whose levels were reduced in BACE1-null mice and significantly improved long-term potentiation and cognitive behaviors. Similarly, mice treated with mGluR1 PAM showed significantly mitigated synaptic deficits caused by BACE1 inhibitors. Together, our data suggest that a therapy combining BACE1 inhibitors for reducing amyloid deposition and an mGluR1 PAM for counteracting BACE1-mediated synaptic deficits appears to be an effective approach for treating AD patients.

scholarly journals Hippocampal mGluR1-dependent long-term potentiation requires NAADP-mediated acidic store Ca2+ signaling

2018 ◽  
Vol 11 (558) ◽  
pp. eaat9093 ◽  
Author(s):  
William J. Foster ◽  
Henry B. C. Taylor ◽  
Zahid Padamsey ◽  
Alexander F. Jeans ◽  
Antony Galione ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Metabotropic Glutamate Receptor 1 ◽  
Phosphatase 2A ◽  
Acidic Organelles ◽  
Activity Dependent

Acidic organelles, such as endosomes and lysosomes, store Ca2+ that is released in response to intracellular increases in the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). In neurons, NAADP and Ca2+ signaling contribute to synaptic plasticity, a process of activity-dependent long-term potentiation (LTP) [or, alternatively, long-term depression (LTD)] of synaptic strength and neuronal transmission that is critical for neuronal function and memory formation. We explored the function of and mechanisms regulating acidic Ca2+ store signaling in murine hippocampal neurons. We found that metabotropic glutamate receptor 1 (mGluR1) was coupled to NAADP signaling that elicited Ca2+ release from acidic stores. In turn, this released Ca2+-mediated mGluR1-dependent LTP by transiently inhibiting SK-type K+ channels, possibly through the activation of protein phosphatase 2A. Genetically removing two-pore channels (TPCs), which are endolysosomal-specific ion channels, switched the polarity of plasticity from LTP to LTD, indicating the importance of specific receptor store coupling and providing mechanistic insight into how mGluR1 can produce both synaptic potentiation and synaptic depression.

Facilitation of long-term potentiation by prior activation of metabotropic glutamate receptors

1996 ◽  
Vol 76 (2) ◽  
pp. 953-962 ◽  
Author(s):  
A. S. Cohen ◽  
W. C. Abraham
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Synaptic Function ◽  
Male Rats ◽  
Dependent Manner ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Term Potentiation ◽  
Gabaa Receptor Antagonist

1. The influence of prior metabotropic glutamate receptor (mGluR) activation on subsequent long-term potentiation (LTP) induction was investigated with the use of the mGluR agonist 1-amino-cyclopentane-1S,3R-dicarboxylic acid (ACPD, 20 microM). Field potential recordings were made in the stratum radiatum of CA1 slices taken from young adult male rats and from which CA3 was routinely dissected. Theta burst stimulation (TBS) just above threshold was used to induce LTP. 2. A 10-min bath application of ACPD begun 30 min before the TBS facilitated the induction of LTP in a dose-dependent manner and resulted in an enhanced magnitude and stability of LTP. 3. ACPD did not enhance the degree of LTP induced by strong TBS, suggesting that it acts to lower the threshold for LTP induction but does not raise the ceiling on the amount of inducible LTP. 4. This priming effect by ACPD was stereo specific and lasted between 1 and 3 h. Synaptic stimulation during the ACPD application was not necessary for the enhancement of LTP. Blockade of N-methyl-D-aspartate receptors (NMDARs) during ACPD application also failed to affect the enhancement of LTP. 5. ACPD-induced priming of LTP was antagonized by L-2-amino-3-phosphonopropionic acid, suggesting an involvement of group I mGluRs. 6. ACPD-induced enhancement of LTP was not secondary to long-lasting changes in NMDAR activation or GABAAergic inhibition, because it was unaffected by the addition of picrotoxin, a gamma-aminobutyric acid-A (GABAA) receptor antagonist, and isolated NMDAR-mediated responses did not show a long-lasting enhancement in response to ACPD application. 7. These data demonstrate that activation of mGluRs can initiate persistent yet covert changes in synaptic function that facilitate the stable induction of LTP.

scholarly journals Altered Short-Term Synaptic Plasticity in Mice Lacking the Metabotropic Glutamate Receptor mGlu7

2002 ◽  
Vol 2 ◽  
pp. 730-737 ◽  
Author(s):  
Trevor J. Bushell ◽  
Gilles Sansig ◽  
Valerie J. Collett ◽  
Herman van der Putten ◽  
Graham L. Collingridge
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Short Term ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Commissural Pathway ◽  
Frequency Facilitation

Eight subtypes of metabotropic glutamate (mGlu) receptors have been identified of which two, mGlu5 and mGlu7, are highly expressed at synapses made between CA3 and CA1 pyramidal neurons in the hippocampus. This input, the Schaffer collateral-commissural pathway, displays robust long-term potentiation (LTP), a process believed to utilise molecular mechanisms that are key processes involved in the synaptic basis of learning and memory. To investigate the possible function in LTP of mGlu7 receptors, a subtype for which no specific antagonists exist, we generated a mouse lacking this receptor, by homologous recombination. We found that LTP could be induced in mGlu7-/- mice and that once the potentiation had reached a stable level there was no difference in the magnitude of LTP between mGlu7-/- mice and their littermate controls. However, the initial decremental phase of LTP, known as short-term potentiation (STP), was greatly attenuated in the mGlu7-/- mouse. In addition, there was less frequency facilitation during, and less post-tetanic potentiation following, a high frequency train in the mGlu7-/- mouse. These results show that the absence of mGlu7 receptors results in alterations in short-term synaptic plasticity in the hippocampus.

Reexamination of the effects of MCPG on hippocampal LTP, LTD, and depotentiation

1995 ◽  
Vol 74 (3) ◽  
pp. 1075-1082 ◽  
Author(s):  
D. K. Selig ◽  
H. K. Lee ◽  
M. F. Bear ◽  
R. C. Malenka
Keyword(s):  
Hippocampal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Low Frequency ◽  
Extracellular Recording ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Frequency Stimulation

1. We examined the effects of the metabotropic glutamate receptor (mGluR) antagonist alpha-methyl-4-carboxyphenylglycine (MCPG) on the induction of long-term potentiation (LTP) long-term depression (LTD), and depotentiation in CA1 hippocampal neurons using extracellular recording techniques. 2. MCPG (500 microM) strongly antagonized the presynaptic inhibitory action of the mGluR agonist 1-aminocyclopentane-(1S,3R)-dicarboxylic acid yet failed to block LTP induced with either tetanic stimulation (100 Hz, 1 s) or theta-burst stimulation. 3. To test the possibility that our failure to block LTP was due to prior activation of a "molecular switch" that in its "on" state obviates the need for mGluR activation to generate LTP, we gave repeated periods of prolonged low-frequency stimulation (LFS; 1 Hz, 10 min), a manipulation reported to turn the switch "off." Although this stimulation saturated LTD, subsequent application of MCPG still failed to block LTP. 4. MCPG did not block LFS-induced depotentiation in older slices (4-6 wk) or LFS-induced LTD in older, young (11-18 days), or neonatal (3-7 days) slices. 5. These results demonstrate that MCPG-sensitive mGluRs are not necessary for the induction of LTP, LTD, or depotentiation in hippocampal CA1 pyramidal cells. The possibility remains, however, that their activation may modify the threshold for the induction of these long-term plastic changes.

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