The Glutamatergic Synaptic Transmission Mediated by Ionotropic Glutamate Receptors in Rats Cerebral Cortex in Behavioral Depression

Background: A dysfunction in glutamate neurotransmission is critical for seizure. Glutamate is the major excitatory drive in the cerebral cortex, where seizures occur. Glutamate acts via (i) ionotropic (iGlu) receptors, which are ligand-gated ion channels mediating fast excitatory synaptic transmission; and (ii) G proteins coupled metabotropic (mGlu) receptors. Objective: To overview the evidence on the role of iGlu receptors in the onset, duration, and severity of convulsive and nonconvulsive seizures to lay the groundwork for novel strategies for drug-resistant epilepsy. Methods: We used PubMed crossed-search for “glutamate receptor and epilepsy” (sorting 3,170 reports), searched for “ionotropic glutamate receptors”, “AMPA receptors”, “NMDA receptors”, “kainate receptors”, “convulsive seizures”, “absence epilepsy”, and selected those papers focusing this Review’s scope. Results: iGlu receptors antagonists inhibit, whereas agonists worsen experimental seizures in various animal species. Clinical development of iGlu receptor antagonists has been limited by the occurrence of adverse effects caused by inhibition of fast excitatory synaptic transmission. To date, only one drug (perampanel) selectively targeting iGlu receptors is marketed for the treatment of focal epilepsy. However, other drugs, such as topiramate and felbamate, inhibit iGlu receptors in addition to other mechanisms. Conclusion: This review is expected to help dissecting those steps induced by iGlu receptors activation, which may be altered to provide antiepileptic efficacy without altering key physiological brain functions, thus improving safety and tolerability of iGlu-receptor directed antiepileptic agents. This effort mostly applies to drug resistant seizures, which impact the quality of life and often lead to status epilepticus, which is a medical urgency.

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Regulation of Ionotropic Glutamate Receptors by Their Auxiliary Subunits

Physiology ◽

10.1152/physiol.00033.2009 ◽

2010 ◽

Vol 25 (1) ◽

pp. 41-49 ◽

Cited By ~ 31

Author(s):

Susumu Tomita

Keyword(s):

Synaptic Plasticity ◽

Synaptic Transmission ◽

Glutamate Receptors ◽

Neurological Disorder ◽

Neural Circuit ◽

Ionotropic Glutamate Receptors ◽

Auxiliary Subunits ◽

The Brain

Glutamate receptors are major excitatory receptors in the brain. Recent findings have established auxiliary subunits of glutamate receptors as critical modulators of synaptic transmission, synaptic plasticity, and neurological disorder. The elucidation of the molecular rules governing glutamate receptors and subunits will improve our understanding of synapses and of neural-circuit regulation in the brain.

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Presynaptic and postsynaptic modulation of glutamatergic synaptic transmission by activation of α1- and β-adrenoceptors in layer V pyramidal neurons of rat cerebral cortex

Synapse ◽

10.1002/syn.20604 ◽

2009 ◽

Vol 63 (4) ◽

pp. 269-281 ◽

Cited By ~ 28

Author(s):

Masayuki Kobayashi ◽

Masao Kojima ◽

Yuko Koyanagi ◽

Kazunori Adachi ◽

Kazuyuki Imamura ◽

...

Keyword(s):

Cerebral Cortex ◽

Synaptic Transmission ◽

Pyramidal Neurons ◽

Rat Cerebral Cortex ◽

Glutamatergic Synaptic Transmission ◽

Layer V

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Synaptic transmission regulated by auxiliary subunits of ionotropic glutamate receptors

Neuroscience Research ◽

10.1016/j.neures.2010.07.271 ◽

2010 ◽

Vol 68 ◽

pp. e9

Author(s):

Susumu Tomita

Keyword(s):

Synaptic Transmission ◽

Glutamate Receptors ◽

Ionotropic Glutamate Receptors ◽

Auxiliary Subunits

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Neurosteroid modulation of ionotropic glutamate receptors and excitatory synaptic transmission

Physiological Research ◽

10.33549/physiolres.931600 ◽

2008 ◽

pp. S49-S57

Author(s):

M Sedláček ◽

M Kořínek ◽

M Petrovič ◽

O Cais ◽

E Adamusová ◽

...

Keyword(s):

Synaptic Transmission ◽

Nmda Receptors ◽

Glutamate Receptors ◽

Ampa Receptors ◽

Transmembrane Domain ◽

Kainate Receptors ◽

Ionotropic Glutamate Receptors ◽

Extracellular Loop ◽

Inhibitory Effects ◽

Chimeric Receptors

Ionotropic glutamate receptors function can be affected by neurosteroids, both positively and negatively. N-methyl-D-aspartate (NMDA) receptor responses to exogenously applied glutamate are potentiated or inhibited (depending on the receptor subunit composition) by pregnenolone sulphate (PS) and inhibited by pregnanolone sulphate (3alpha5betaS). While PS effect is most pronounced when its application precedes that of glutamate, 3alpha5betaS only binds to receptors already activated. Synaptically activated NMDA receptors are inhibited by 3alpha5betaS, though to a lesser extent than those tonically activated by exogenous glutamate. PS, on the other hand, shows virtually no effect on any of the models of synaptically activated NMDA receptors. The site of neurosteroid action at the receptor molecule has not yet been identified, however, the experiments indicate that there are at least two distinct extracellularly located binding sites for PS mediating its potentiating and inhibitory effects respectively. Experiments with chimeric receptors revealed the importance of the extracellular loop connecting the third and the fourth transmembrane domain of the receptor NR2 subunit for the neurosteroid action. alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors are inhibited by both PS and 3alpha5betaS. These neurosteroids also affect AMPA receptors-mediated synaptic transmission, however, in a rather indirect way, through presynaptically located targets of action.

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

Journal of Neurophysiology ◽

10.1152/jn.1996.76.6.3834 ◽

1996 ◽

Vol 76 (6) ◽

pp. 3834-3841 ◽

Cited By ~ 39

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.

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Ketamine disrupts neuromodulatory control of glutamatergic synaptic transmission

10.1101/341172 ◽

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.

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