Hippocampal GluR1 associates with behavior in the elevated plus maze and shows sex differences

Abstract

The hippocampus is involved in anxiety as well as spatial memory formation and is sexually dimorphic. Female rats typically show less anxiety in elevated plus maze procedure (EPM), a standard animal model of anxiety. Many intracellular proteins, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 and the cyclic AMP response element-binding protein (CREB), in hippocampus contribute to memory formation. However, less is known about the roles for hippocampal GluR1 and CREB in anxiety. We examined behavior in EPM in male and female rats and obtained hippocampal tissue samples to determine levels of GluR1 and CREB with western blots. EPM results showed that female rats exhibited less anxiety-like behaviors than male rats. Further, behaviors in EPM were significantly correlated with hippocampal GluR1 levels, but not with CREB. Yet, both proteins showed sex differences with lower levels in female rats. These data not only suggest some potential bases for sex differences in behaviors to which the hippocampus contributes but demonstrate that there is a strong association between hippocampal GluR1 levels and anxiety as assessed with EPM.

Figure 1

Mean (± S.E.M.) times (sec) spent in the open and closed arms as well as center zone of the elevated plus maze are shown for female (closed bars) and male (open bars) rats in the figure. Female rats spend more time in the open arm and less time in the closed arm than male rats but do not differ in time spent in the center zone. (see text for statistics). * represents significant sex differences.

Figure 2

Mean (± S.E.M.) arbitrary densitometry units reflecting GluR1 levels for left, right, and total hippocampus are shown for female (closed symbols) and male (open symbols) rats in the left figure. Mean (± S.E.M.) arbitrary densitometry units reflecting CREB levels for left, right, and total hippocampus are shown in the right figure. Female rats show lower GluR1 levels than male rats in the left hippocampus and in total hippocampus but do no differ in GluR1 levels in right hippocampus. There is also a trend for male, but not female rats, to have higher GluR1 levels in left vs. right hippocampus. Female rats show lower CREB levels than male rats in the right hippocampus and in total hippocampus but do no differ in CREB levels in left hippocampus (see text for statistics). * represents significant sex differences and # represents significant side differences for male rats.

Figure 3

Representative bands of GluR1 and CREB from right and left hippocampi of male and female rats are shown.

Figure 4

The correlation of time (min) spent in the open arm with total hippocampal levels of GluR1 is plotted in the left figure. The data show a significant negative association with an R² greater than 0.49. The correlation of total distance traveled (m) with total hippocampal levels of GluR1 is plotted in the right figure. The data show a significant positive association with an R² greater than 0.25. Closed symbols represent individual female rats and open symbols represent individual male rats.