Back to Search
Start Over
Ketamine disrupts neuromodulatory control of glutamatergic synaptic transmission.
Ketamine disrupts neuromodulatory control of glutamatergic synaptic transmission.
- Source :
-
PloS one [PLoS One] 2019 Mar 13; Vol. 14 (3), pp. e0213721. Date of Electronic Publication: 2019 Mar 13 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- A 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 N-methyl-D-aspartate (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, levels of the neuromodulatory Regulator of G-protein Signaling (RGS4) are dramatically reduced. This loss of RGS4 activity is associated with disruption of the normal compartmentalization of synaptic neuromodulation. Thus, under control conditions, α2 adrenergic receptors and type B γ-aminobutyric acid (GABAB) receptors selectively inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) -type glutamate receptors (AMPARs) and NMDARs, respectively. After ketamine administration and reduction in RGS4 activity, this selectivity is lost, with both modulatory systems broadly inhibiting glutamatergic transmission. These results suggest a novel mechanism by which ketamine may influence synaptic signaling and provide new avenues for the exploration of therapeutics directed at treating neuropsychiatric disorders, such as depression.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- Animals
Antidepressive Agents administration & dosage
Antidepressive Agents pharmacology
Behavior, Animal
Brain drug effects
Female
Ketamine administration & dosage
Male
Mice
Mice, Inbred C57BL
N-Methylaspartate
Neurons metabolism
Neurotransmitter Agents administration & dosage
Neurotransmitter Agents pharmacology
Receptors, AMPA metabolism
Receptors, GABA metabolism
Signal Transduction
Swimming
Synapses metabolism
Synaptic Potentials drug effects
Video Recording
Depression drug therapy
Glutamine metabolism
Ketamine pharmacology
Prefrontal Cortex drug effects
Synaptic Transmission drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 14
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 30865708
- Full Text :
- https://doi.org/10.1371/journal.pone.0213721