Emerging roles of Fgf14 in behavioral control

Abstract

Sexual disturbances, and aggressivity are a major social problem. However, the molecular mechanisms involved in the control of these behaviors are largely unknown. FGF14, which is an intracellular protein controlling neuronal excitability and synaptic transmission, has been implied in neurologic and psychiatric disorders. Mice with Fgf14 deletion show blunted responses to drugs of abuse. By behavioral tests we show that male Fgf14 knockout mice have a marked reduction of several behaviors including aggressivity and sexual behavior. Other behaviors driven by spontaneous initiative like burying novel objects and spontaneous digging and climbing are also reduced in Fgf14 knockout mice. These deficits cannot be attributed to a generalized decrease of activity levels, because in the open field test Fgf14 knockout mice have the same spontaneous locomotion as wild types and increased rearing. Our results show that Fgf14 is important to preserve a set of behaviors and suggest that fine tuning of neuronal function by Fgf14 is an important mechanism of control for such behaviors.

Keywords: Aggressivity; Fgf14; Mouse; Sexual behavior; Sociability; Spontaneous behavior.

Fig. 1.

Experimental timeline showing the sequence of behavioral tests delivered to the animals.

Fig. 2.

Rearing behavior observed in 10 min session. A–C. Rearing-wall behavior: Bars represent mean ± SEM of (A) rearing-wall time (p < 0.05), (B) number of episodes and (C) duration of each rearing-wall episode (p < 0.001). Rearing central structure behavior (D–F): (D) rearing-central structure time (p < 0.01), (E) number of episodes (p < 0.05) and (F) duration of each rearing-central structure episode (p < 0.001). Free rearing behavior (G–I): (G) free rearing time, (H) number of episodes and (I) duration of each free rearing episode of (p < 0.05).

Fig. 3.

Fgf14^−/− mice show a reduction in digging behavior. (A) Time spent in digging behavior (p < 0.01). (B) Number of digging episodes (p < 0.001). (C) Duration of each digging episode (p > 0.05).

Fig. 4.

Fgf14^−/− mice show a reduction in climbing behavior. (A) Bars represent mean ± SEM of total time spent climbing during the 10 min session. The total time spent climbing is significantly reduced compared to wild type mice * p < 0.05. (B) Fgf14^−/− mice display a reduced number of climbing episodes ** p < 0.01. (C) Bars show no significant difference between genotypes in the mean duration of each climbing episode p > 0.05.

Fig. 5.

Fgf14^−/− mice bury a smaller number of marbles in 30 min of test compared to their wild type littermates. The bars represent mean ± SEM. *** p < 0.001.

Fig. 6.

Fgf14^−/− male mice show a reduced sexual interaction. (a) The latency for sexual interaction is increased while the mounting duration is decreased (b). The number of mounts (c), and the duration of each episode (d) are significantly fewer in Fgf14^−/− mice compared to their wild type littermates. (e) The number of males that had a sexual approach was significantly lower in Fgf14^−/− mice. Fgf14^−/− mice during the test spent more time in passive behavior (f). The bars represent mean ± SEM. * p < 0.05; ** p < 0.01; *** p < 0.001.

Fig. 7.

Fgf14^−/− male mice show a reduced aggressivity in the resident intruder test. Bars represent means ± SEM of time (in seconds) spent in attack (a) and threat (d), number of episodes for attack (b) and threat (e), and mean duration of each episode for attack (c) and threat (f). (g) Duration of social behavior exhibited during the test. (h) Relative duration of inter-individual interaction types. (i) Representative Nissl-stained sections used to measure the size of the amygdala (calibration bar: 250 μm). (j) Volume of the amygdala in Fgf14^−/− and wild type mice. The bars represent mean ± SEM. * p < 0.05; ** p < 0.01; *** p < 0.001.

Fig. 8.

Fgf14^−/− male mice show normal sociability, locomotor activity, exploratory behavior and time in center. (a) In the three chambers test both wild type and Fgf14^−/− mice show a preference for a stranger mouse relative to an object (an empty wire cup identical to the one used to restrict the stranger mouse). (b) (left) In a novel open arena the locomotor activity related to the exploratory behavior and (right) the time in center are indistinguishable in Fgf14^−/− relative to wild type mice. The bars represent mean ± SEM. ** p < 0.01.

Fig. 9.

Drd1, Drd2 and Slc6a3 gene expression in the mPFC (a, d, g), Acb (b, e, h) and CPu (c, f, i) in wild type and Fgf14^−/− mice. There were no significant changes for each gene expression in all the brain regions analyzed. Data are expressed as mean ± SEM.