Increased anxiety and synaptic plasticity in estrogen receptor beta -deficient mice

Abstract

Estrogens are powerful modulators of neuronal physiology and in humans may affect a broad range of functions, including reproductive, emotional, and cognitive behaviors. We studied the contribution of estrogen receptors (ERs) in modulation of emotional processes and analyzed the effects of deleting ERalpha or ERbeta in mice. Behavior consistent with increased anxiety was observed principally in ERbeta mutant females and was associated with a reduced threshold for the induction of synaptic plasticity in the basolateral amygdala. Local increase of 5-hydroxytryptamine 1a receptor expression in medial amygdala may contribute to these changes. Our data show that, particularly in females, there is an important role for ERbeta-mediated estrogen signaling in the processing of emotional behavior.

Figure 1

Behavioral analysis of ERα and ERβ null mutant mice in the open field. The latency to move to the edge of the OF after being placed in the center at the beginning of the test was scored (a), and the rate of stretching during this period on the first day of testing was expressed as stretches per s (b). Thygmotaxis (c), locomotion (d), and rearing (e) all were recorded in WT (n = 26, n = 24), ERα^−/− (n = 9, n = 7), and ERβ^−/− (n = 11, n = 15) females and males, respectively, and were expressed as means ± SEM. ***, P < 0.001; **, P < 0.01; *, P < 0.05 with respect to WT female group.

Figure 2

Behavioral evaluation of ERα^−/− and ERβ^−/− mice in the elevated plus maze. The percent of time mice spent in the open arm (a) and the number of head dips (b) were expressed as means ± SEM. ***, P < 0.001; **, P < 0.01; *, P < 0.05 with respect to WT female group.

Figure 3

Effects of ERβ deletion on synaptic physiology in the amygdala. Input–output curves recorded in the absence or presence of 3 μM bicuculline (a), induction of LTP by weak tetanus (b), strong tetanus (c), and weak tetanus in the presence of 3 μM bicuculline (d) were collected from seven ERβ^−/− and eight WT females except in the bicuculline experiment, where three ERβ mutant and four WT females were used. Data were expressed as means ± SEM.

Figure 4

Immunohistochemical detection of 5-HT_1a receptors in the medial amygdala. The regions of selected brain sections are presented for histological identification (A and D). Sections from WT (B and C) and ERβ^−/− (E and F) females were stained for the 5-HT_1a receptor. Fluorescence in the medial amygdala was represented as the percent of the fluorescence in VPL (G). All of the cells labeled for 5-HT_1a in medial amygdala were represented as the percent of total cell number in this region as determined by DAPI staining (H). Me, medial amygdala; MePV, medical amygdala posteroventral; opt, optic tract. (Bar: 100 μm in A, B, D, and E; 50 μm in C and F.)