Elevated level of metabotropic glutamate receptor 2/3 in the prefrontal cortex in major depression

Abstract

Clinical, postmortem and preclinical research strongly implicates dysregulation of glutamatergic neurotransmission in major depressive disorder (MDD). Recently, metabotropic glutamate receptors (mGluRs) have been proposed as attractive targets for the discovery of novel therapeutic approaches against depression. The aim of this study was to examine mGluR2/3 protein levels in the prefrontal cortex (PFC) from depressed subjects. In addition, to test whether antidepressants influence mGluR2/3 expression we also studied levels of mGluR2/3 in fluoxetine-treated monkeys. Postmortem human prefrontal samples containing Brodmann's area 10 (BA10) were obtained from 11 depressed and 11 psychiatrically healthy controls. Male rhesus monkeys were treated chronically with fluoxetine (dose escalated to 3mg/kg, p.o.; n=7) or placebo (n=6) for 39 weeks. The mGluR2/3 immunoreactivity was investigated using Western blot method. There was a robust (+67%) increase in the expression of the mGlu2/3 protein in the PFC of depressed subjects relative to healthy controls. The expression of mGlu2/3 was unchanged in the PFC of monkeys treated with fluoxetine. Our findings provide the first evidence that mGluR2/3 is elevated in the PFC in MDD. This observation is consistent with reports showing that mGluR2/3 antagonists exhibit antidepressant-like activity in animal models and demonstrates that these receptors are promising targets for the discovery of novel antidepressants.

Figure 1

Representative immunoblot of mGluR2/3 and actin from three male pairs of control and MDD subjects (A). Scatter plot of mGluR2/3 protein levels normalized to actin (B). The average mGluR2,3/actin ratio from subjects with MDD (n=11) was significantly higher (+67%) than that of matched controls (n=11). Normalized optical density values for the individual subjects (circles) and mean values (horizontal lines) are presented. Cont, healthy control; MDD, major depressive disorder; M, male.

Figure 2

mGluR2/3 immunoreactivity from individual major depressive disorder subjects expressed as percentages of values from individually paired control subjects. Each bar is an average of duplicate comparisons.

Figure 3

Representative immunoblot of mGluR2/3 and actin from two vehicle and two fluoxetine treated monkeys (A). Scatter plot of mGluR2/3 protein levels normalized to actin (B). The average mGluR2,3/actin ratio from fluoxetine treated monkeys (n=7) was unchanged compared to vehicle group (n=6). Normalized optical density values for the individual monkeys (circles) and mean values (horizontal lines) are presented. V, vehicle; F, fluoxetine.