scholarly journals mTORC1 and mTORC2 regulate distinct aspects of glutamatergic synaptic transmission

2019 ◽  
Author(s):  
Matthew P. McCabe ◽  
Erin R. Cullen ◽  
Caitlynn M. Barrows ◽  
Amy N. Shore ◽  
Katharine I. Tooke ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Mtor Signaling ◽  
Major Mechanism ◽  
Presynaptic Function ◽  
Glutamatergic Synaptic Transmission ◽  
Presynaptic Release ◽  
Neuron Growth ◽  
Cell Growth And Proliferation ◽  
Synaptic Vesicle Release

AbstractAlthough mTOR signaling is known as a broad regulator of cell growth and proliferation, in neurons it regulates synaptic transmission, which is thought to be a major mechanism through which altered mTOR signaling leads to neurological disease. Although previous studies have delineated postsynaptic roles for mTOR, whether it regulates presynaptic function is largely unknown. Moreover, the mTOR kinase operates in two complexes, mTORC1 and mTORC2, suggesting that mTOR’s role in synaptic transmission may be complex-specific. To better understand each complex’s role in synaptic transmission, we genetically inactivated mTORC1 or mTORC2 in cultured mouse glutamatergic hippocampal neurons. Inactivation of either complex reduced neuron growth and evoked EPSCs, however, mTORC1 exerted its effects on eEPSCs at the postsynapse and mTORC2 at the presynapse. Furthermore, inactivation of each complex altered specific modes of synaptic vesicle release, suggesting that mTORC1 and mTORC2 differentially modulate postsynaptic responsiveness and presynaptic release to optimize glutamatergic synaptic transmission.

scholarly journals Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Matthew P McCabe ◽  
Erin R Cullen ◽  
Caitlynn M Barrows ◽  
Amy N Shore ◽  
Katherine I Tooke ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Mtor Signaling ◽  
Postsynaptic Inhibition ◽  
Major Mechanism ◽  
Presynaptic Function ◽  
Glutamatergic Synaptic Transmission ◽  
Presynaptic Release ◽  
Neuron Growth ◽  
Cell Growth And Proliferation

Although mTOR signaling is known as a broad regulator of cell growth and proliferation, in neurons it regulates synaptic transmission, which is thought to be a major mechanism through which altered mTOR signaling leads to neurological disease. Although previous studies have delineated postsynaptic roles for mTOR, whether it regulates presynaptic function is largely unknown. Moreover, the mTOR kinase operates in two complexes, mTORC1 and mTORC2, suggesting that mTOR’s role in synaptic transmission may be complex-specific. To better understand their roles in synaptic transmission, we genetically inactivated mTORC1 or mTORC2 in cultured mouse glutamatergic hippocampal neurons. Inactivation of either complex reduced neuron growth and evoked EPSCs (eEPSCs), however, the effects of mTORC1 on eEPSCs were postsynaptic and the effects of mTORC2 were presynaptic. Despite postsynaptic inhibition of evoked release, mTORC1 inactivation enhanced spontaneous vesicle fusion and replenishment, suggesting that mTORC1 and mTORC2 differentially modulate postsynaptic responsiveness and presynaptic release to optimize glutamatergic synaptic transmission.

Methamphetamine modulates glutamatergic synaptic transmission in rat primary cultured hippocampal neurons

2014 ◽  
Vol 1582 ◽  
pp. 1-11 ◽  
Author(s):  
Shuzhuo Zhang ◽  
Yuelei Jin ◽  
Xiaoyan Liu ◽  
Lujia Yang ◽  
Zhi juan Ge ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Glutamatergic Synaptic Transmission ◽  
Cultured Hippocampal Neurons

scholarly journals The soluble neurexin-1β ectodomain causes calcium influx and augments dendritic outgrowth and synaptic transmission

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Keimpe D. B. Wierda ◽  
Trine L. Toft-Bertelsen ◽  
Casper R. Gøtzsche ◽  
Ellis Pedersen ◽  
Irina Korshunova ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Hippocampal Neurons ◽  
Prolonged Exposure ◽  
Calcium Influx ◽  
Dependent Manner ◽  
Cellular Effects ◽  
Glutamatergic Neurons ◽  
Readily Releasable Pool ◽  
Presynaptic Release ◽  
Activity Dependent

Abstract Classically, neurexins are thought to mediate synaptic connections through trans interactions with a number of different postsynaptic partners. Neurexins are cleaved by metalloproteases in an activity-dependent manner, releasing the soluble extracellular domain. Here, we report that in both immature (before synaptogenesis) and mature (after synaptogenesis) hippocampal neurons, the soluble neurexin-1β ectodomain triggers acute Ca2+-influx at the dendritic/postsynaptic side. In both cases, neuroligin-1 expression was required. In immature neurons, calcium influx required N-type calcium channels and stimulated dendritic outgrowth and neuronal survival. In mature glutamatergic neurons the neurexin-1β ectodomain stimulated calcium influx through NMDA-receptors, which increased presynaptic release probability. In contrast, prolonged exposure to the ectodomain led to inhibition of synaptic transmission. This secondary inhibition was activity- and neuroligin-1 dependent and caused by a reduction in the readily-releasable pool of vesicles. A synthetic peptide modeled after the neurexin-1β:neuroligin-1 interaction site reproduced the cellular effects of the neurexin-1β ectodomain. Collectively, our findings demonstrate that the soluble neurexin ectodomain stimulates growth of neurons and exerts acute and chronic effects on trans-synaptic signaling involved in setting synaptic strength.

scholarly journals Parkinson’s disease-linked Parkin mutations impair glutamatergic synaptic transmission and plasticity

2018 ◽  
Author(s):  
Mei Zhu ◽  
Giuseppe P. Cortese ◽  
Clarissa L. Waites
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Synaptic Transmission ◽  
Ampa Receptor ◽  
Hippocampal Neurons ◽  
Receptor Trafficking ◽  
Synaptic Function ◽  
Glutamatergic Synaptic Transmission ◽  
The Impact ◽  
Ampa Receptor Trafficking

AbstractParkinson’s disease (PD)-associated E3 ubiquitin ligase Parkin is enriched at glutamatergic synapses, where it ubiquitinates multiple substrates, suggesting that its mutation/loss-of-function could contribute to the etiology of PD by disrupting excitatory neurotransmission. Here, we evaluate the impact of four common PD-associated Parkin point mutations (T240M, R275W, R334C, G430D) on glutamatergic synaptic function in hippocampal neurons. We find that expression of these point mutants in Parkin-deficient and -null backgrounds alters NMDA and AMPA receptor-mediated currents and cell-surface levels, and prevents the induction of long-term depression. Mechanistically, we demonstrate that Parkin regulates NMDA receptor trafficking through its ubiquitination of GluN1, and that all four mutants are impaired in this ubiquitinating activity. Furthermore, Parkin regulates synaptic AMPA receptor trafficking via its binding and retention of the postsynaptic scaffold Homer1, and all mutants are similarly impaired in this capacity. Our findings demonstrate that pathogenic Parkin mutations disrupt glutamatergic synaptic transmission and plasticity by impeding NMDA and AMPA receptor trafficking, and through these effects likely contribute to the pathophysiology of PD inPARK2patients.

scholarly journals Blockade of NR2B-Containing NMDA Receptors Prevents BDNF Enhancement of Glutamatergic Transmission in Hippocampal Neurons

1999 ◽  
Vol 6 (3) ◽  
pp. 257-266 ◽  
Author(s):  
Robert A. Crozier ◽  
Ira B. Black ◽  
Mark R. Plummer
Keyword(s):  
Nmda Receptor ◽  
Synaptic Transmission ◽  
Nmda Receptors ◽  
Hippocampal Neurons ◽  
Nmda Receptor Antagonist ◽  
Receptor Subtype ◽  
Patch Clamp Recording ◽  
Inhibitory Peptide ◽  
Whole Cell Patch Clamp ◽  
Glutamatergic Synaptic Transmission

Application of brain-derived neurotrophic factor (BDNF) to hippocampal neurons has profound effects on glutamatergic synaptic transmission. Both pre- and postsynaptic actions have been identified that depend on the age and type of preparation. To understand the nature of this diversity, we have begun to examine the mechanisms of BDNF action in cultured dissociated embryonic hippocampal neurons. Whole-cell patch-clamp recording during iontophoretic application of glutamate revealed that BDNF doubled the amplitude of induced inward current. Coexposure to BDNF and the NMDA receptor antagonist AP-5 markedly reduced, but did not entirely prevent, the increase in current. Coexposure to BDNF and ifenprodil, an NR2B subunit antagonist, reproduced the response observed with AP-5, suggesting BDNF primarily enhanced activity of NR2B-containing NMDA receptors with a lesser effect on non-NMDA receptors. Protein kinase involvement was confirmed with the broad spectrum inhibitor staurosporine, which prevented the response to BDNF. PKCI19-31 and H-89, selective antagonists of PKC and PKA, had no effect on the response to BDNF, whereas autocamtide-2-related inhibitory peptide, an antagonist of CaM kinase II, reduced response magnitude by 60%. These results demonstrate the predominant role of a specific NMDA receptor subtype in BDNF modulation of hippocampal synaptic transmission.

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