Impaired glycinergic synaptic transmission and enhanced inflammatory pain in mice with reduced expression of vesicular GABA transporter (VGAT).

Abstract

Loading of GABA and glycine into synaptic vesicles via the vesicular GABA transporter (VGAT) is an essential step in inhibitory neurotransmission. As a result of the evidence linking alterations in GABAergic and/or glycinergic neurotransmission to various pain disorders, we investigated the possible influence of down-regulation of VGAT on pain threshold and behavioral responses in mice. The phenotypes of heterozygous VGAT knockout [VGAT(+/-)] mice were compared with wild-type (WT) mice using behavioral assays. In addition, GABAergic and glycinergic miniature inhibitory postsynaptic currents (mIPSCs) were recorded in dorsal horn neurons. Western blot analysis confirmed significant reduction of VGAT protein levels in VGAT(+/-) mice. However, high-performance liquid chromatography revealed that glutamate, GABA, and glycine contents in the whole brain and spinal cord were normal in VGAT(+/-) mice. Behavioral analysis of VGAT(+/-) mice showed unchanged motor coordination, anxiety, memory performance, and anesthetic sensitivity to propofol and ketamine, although thermal nociception and inflammatory pain were enhanced. Patch-clamp recordings revealed that the frequency and amplitude of glycinergic mIPSCs in lamina II neurons were reduced in VGAT(+/-) mice. Genotype differences in glycinergic mIPSCs were more evident during sustained stimulation by solutions with high potassium levels, suggesting that the estimated size of the readily releasable pool of glycine-containing vesicles was reduced in VGAT(+/-) mice. These results provide genetic, behavioral, and electrophysiological evidence that VGAT-mediated inhibitory drive alters very specific forms of sensory processing: those related to pain processing. More close examination will be needed to verify the possibility of VGAT as a new therapeutic target for the treatment of inflammatory pain.

• Authors: Makiko Hardy Yamada, Koichi Nishikawa, Kazuhiro Kubo, Yuchio Yanagawa, Shigeru Saito
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 81 Issue 4 Pg. 610-9 (Apr 2012) ISSN: 1521-0111 [Electronic] United States
• PMID: 22275517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Vesicular Inhibitory Amino Acid Transport Proteins
• Viaat protein, mouse
• Glycine

Topics

• Animals
• Behavior, Animal
• Blotting, Western
• Down-Regulation
• Glycine (physiology)
• Inflammation (physiopathology)
• Mice
• Mice, Knockout
• Pain (physiopathology)
• Spinal Cord (physiopathology)
• Synaptic Transmission (physiology)
• Vesicular Inhibitory Amino Acid Transport Proteins (genetics, physiology)