scholarly journals Ketamine disrupts neuromodulatory control of glutamatergic synaptic transmission

2018 ◽  
Author(s):  
Gyorgy Lur ◽  
Michael J. Higley
Keyword(s):  
Synaptic Transmission ◽  
Glutamate Receptors ◽  
Adrenergic Receptors ◽  
G Protein Signaling ◽  
Rodent Models ◽  
Protein Signaling ◽  
Glutamatergic Transmission ◽  
Glutamatergic Synapses ◽  
Glutamatergic Synaptic Transmission ◽  
Full Complement

AbstractA growing body of literature has demonstrated the potential for ketamine in the treatment of major depression. Sub-anesthetic doses produce rapid and sustained changes in depressive behavior, both in patients and rodent models, associated with reorganization of glutamatergic synapses in the prefrontal cortex (PFC). While ketamine is known to regulate NMDA-type glutamate receptors (NMDARs), the full complement of downstream cellular consequences for ketamine administration are not well understood. Here, we combine electrophysiology with 2-photon imaging and glutamate uncaging in acute slices of mouse PFC to further examine how ketamine alters glutamatergic synaptic transmission. We find that four hours after ketamine treatment, glutamatergic synapses themselves are not significantly affected. However, expression levels of the neuromodulatory Regulator of G-protein Signaling (RGS4) are dramatically reduced. This loss of RGS4 activity disrupts the normal compartmentalization of synaptic neuromodulation. Thus, under control conditions, α2 adrenergic receptors and GABAB receptors selectively inhibit AMPA-type glutamate receptors (AMPARs) and NMDARs, respectively. After ketamine-induced loss of RGS4 activity, this selectivity is lost, with both modulatory systems broadly inhibiting glutamatergic transmission. These results demonstrate a novel mechanism by which ketamine can influence synaptic signaling and provide new avenues for the exploration of therapeutics directed at treating neuropsychiatric disorders, such as depression.

Activation of pharmacologically distinct metabotropic glutamate receptors depresses reticulospinal-evoked monosynaptic EPSPs in the lamprey spinal cord

1996 ◽  
Vol 76 (6) ◽  
pp. 3834-3841 ◽  
Author(s):  
P. Krieger ◽  
A. el Manira ◽  
S. Grillner
Keyword(s):  
Spinal Cord ◽  
Synaptic Transmission ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Input Resistance ◽  
Spinal Neurons ◽  
Metabotropic Glutamate ◽  
Apparent Change ◽  
Glutamatergic Synaptic Transmission ◽  
Presynaptic Mechanisms

1. Different metabotropic glutamate receptors (mGluRs) can modulate synaptic transmission in different regions in the CNS, but their roles at individual synaptic connections have not been detailed. We used paired intracellular recordings from reticulospinal axons and their postsynaptic target neurons in the lamprey spinal cord to investigate the effects of mGluR activation on glutamatergic synaptic transmission. 2. The mGluR agonists (1S,3R)-1-aminocyclopentane-1,3-dicarboxyylic acid [(1S,3R)-ACPD] and L(+)-2-amino-4-phosphonobutyric acid (L-AP4) both reduced the amplitude of monosynaptic excitatory postsynaptic potentials (EPSPs) elicited by stimulation of single reticulospinal axons. The depression of monosynaptic unitary EPSPs occurred without any apparent change in the input resistance of postsynaptic neurons. Furthermore, the mGluR agonists did not affect the amplitude of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced depolarizations. Taken together, these results thus suggest that (1S,3R)-ACPD and L-AP4 depress reticulospinal synaptic transmission via presynaptic mechanisms. 3. (2S,1'S,2'S)-2-(carboxycyclopropyl) glycine (L-CCG-I), which selectively activates group II mGluRs, also reduced the amplitude of reticulospinal-evoked EPSPs without any apparent change in the input resistance or membrane potential of the postsynaptic neuron. 4. The mGluR antagonist alpha-methyl-L-AP4 blocked the depression induced by L-AP4 but not that induced by (1S,3R)-ACPD. Furthermore, the effects of coapplication of (1S,3R)-ACPD and L-AP4 were additive, suggesting that they inhibit synaptic transmission by an action on pharmacologically distinct mGluRs. 5. These results provide evidence for the colocalization of at least two different subtypes of presynaptic mGluRs on a single reticulospinal axon in the lamprey. These presynaptic mGluRs could serve as glutamatergic autoreceptors limiting the extent of reticulospinal-mediated excitation of spinal neurons.

scholarly journals Norepinephrine activates β1-adrenergic receptors localized to the inner nuclear membrane in cortical astrocytes

2021 ◽  
Author(s):  
Kelsey C Benton ◽  
Daniel S Wheeler ◽  
Beliz Kurtoglu ◽  
Mahshid Bagher Zadeh Ansari ◽  
Daniel P Cibich ◽  
...  
Keyword(s):  
Nuclear Membrane ◽  
Adrenergic Receptors ◽  
Organic Cation Transporter ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Nuclear Compartment ◽  
Nuclear Membranes ◽  
The Central Nervous System ◽  
Organic Cation Transporter 3 ◽  
Powerful Mechanism

Studies in cardiomyocytes have established that adrenergic receptors, conventionally thought to initiate signaling events exclusively from the plasma membrane, can also localize to and signal from the nuclear membrane. Activation of these receptors by their endogenous cationic ligands requires transmembrane uptake mediated by organic cation transporter 3 (OCT3). We have demonstrated that OCT3 is densely localized to outer nuclear membranes in neurons and astrocytes, suggesting that nuclear adrenergic signaling is also present in the central nervous system. In this study, we examined the subcellular localization of β1-adrenergic receptors, their G-protein signaling partners, and catecholamine transporters in mouse astrocytes. We identified a population of β1-adrenergic receptors localized to astrocyte inner nuclear membranes. We demonstrated that key components of Gs-mediated signaling are localized to the nuclear compartment and identified OCT3 and other catecholamine transporters localized to plasma and nuclear membranes. Treatment of astrocytes with NE induced rapid increases in nuclear PKA activity which were blocked by pretreatment with inhibitors of catecholamine transport. These data indicate that nuclear adrenergic receptors are functionally coupled to Gs-coupled signaling mediators and that their activation by norepinephrine requires transporter-mediated uptake. These receptors represent a powerful mechanism by which norepinephrine may alter astrocyte gene expression and brain function.

scholarly journals Danish and British dementia ITM2b/BRI2 mutations reduce BRI2 protein stability and impair  glutamatergic synaptic transmission

2020 ◽  
pp. jbc.RA120.015679
Author(s):  
Tao Yin ◽  
Wen Yao ◽  
Alexander D Lemenze ◽  
Luciano D'Adamio
Keyword(s):  
Synaptic Transmission ◽  
Glutamate Release ◽  
Physiological Role ◽  
Integral Membrane Protein ◽  
Glutamatergic Transmission ◽  
Excitatory Neurotransmitter ◽  
Pathogenic Mutations ◽  
Glutamatergic Synaptic Transmission

Mutations in Integral membrane protein 2B (ITM2b/BRI2) gene causes familial British and Danish dementia (FBD and FDD), autosomal dominant disorders characterized by progressive cognitive deterioration. Two pathogenic mechanisms, which may not be mutually exclusive, have been proposed for FDD and FBD: 1) loss of BRI2 function; 2) accumulation of amyloidogenic mutant BRI2-derived peptides, but the mechanistic details remain unclear. We have previously reported a physiological role of BRI2 in excitatory synaptic transmission at both presynaptic termini and postsynaptic termini. To test whether pathogenic ITM2b mutations affect these physiological BRI2 functions, we analyzed glutamatergic transmission in FDD and FBD knock-in mice, which carry pathogenic FDD and FBD mutations into the mouse endogenous Itm2b gene. We show that in both mutant lines, spontaneous glutamate release and AMPAR-mediated responses are decreased, while short-term synaptic facilitation is increased, effects similar to those observed in Itm2bKO mice. In vivo and in vitro studies show that both pathogenic mutations alter maturation of BRI2 resulting in reduced levels of functional mature BRI2 protein at synapses. Collectively, the data show that FDD and FBD mutations cause a reduction of BRI2 levels and function at synapses, which results in reduced glutamatergic transmission. Notably, other genes mutated in Familial dementia, such as APP, PSEN1/PSEN2, are implicated in glutamatergic synaptic transmission, a function that is altered by pathogenic mutations. Thus, defects in excitatory neurotransmitter release may represent a general and convergent mechanism leading to neurodegeneration. Targeting these dysfunction may offer a unique disease modifying method of therapeutic intervention in neurodegenerative disorders.

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