Synaptic plasticity within ACC and insular cortex (IC) is a key cellular mechanism for chronic pain [8, 9]. Most of previous studies were carried out in adult male mice and these results are not able to explain the increasing reports of gender differences in pain. In the present study, we compared the gender differences at synaptic plasticity level between female and male mice in the ACC. We found that there was no gender difference in post-LTP between female and male mice. For LTD, we found that in comparison with female ACC, the number of channels with LTD was significantly higher in male mice than that in female mice.
In our present work, we compared the characteristics of LTP in the female and male mice. We found that TBS can induce similar LTP in female as in male mice. Furthermore, both percentage of channels that undergoing LTP and the magnitude of LTP are similar between male and female mice. Our LTP results from male mice are similar to LTP reported in our previous reports [14, 21]. These results clearly indicate that there is no significant difference in LTP in the ACC between male and female adult mice. However, in other brain areas such like hippocampus and amygdala, gender-related differences in LTP have been reported, although some results are contradictory [27–30]. For example, Chen et al. showed that female mice had a greater LTP magnitude in amygdala as compared to that in male mice [29]. But Bender et al. found that there was no gender difference for LTP in amygdala [30]. These inconsistent results of gender differences in synaptic plasticity may because of the different pathway and the different stimulation paradigm employed.
Another similarity between male and female mice is the recruitment of silent synapses after the induction of L-LTP [14, 20]. Our recent study reported that phosphorylation at s845 site of glutamate receptor 1 (GluA1) and possible postsynaptic trafficking of AMPA receptor may contribute to the recruitment of silent response [14, 31, 32]. In addition to N-methyl-D-aspartate (NMDA) receptor dependent post-LTP we reported in this study, there are other forms of LTP in the ACC [8, 9, 33]. We cannot rule out possible differences in other forms of LTP such as NMDAR independent LTPs [33, 34] between male and female mice. Future studies are clearly needed.
LTD is another kind of synaptic plasticity in the ACC. In the present study, we found that the amplitude of LTD is similar between female and male mice. However, the number of LTD expression sites in male mice was significantly higher than that in female mice, indicating there is a gender difference in network plasticity between female and male mice. This implies that female and male mice may have gender difference in the development of ACC structure. The gender difference in the structure and function of ACC is also confirmed by functional magnetic resonance imaging (fMRI). In the control of negative emotion, there was a significantly stronger activity in the areas of cognitive control in men, including ACC area [35, 36].
In summary, our results demonstrated that there was no gender difference in LTP in ACC, but the expression of LTD in male mice was slightly higher than that in female mice. Previous studies have shown that chronic pain is related to the saturated late component of LTP and the inhibition of LTD in ACC [11, 13, 16, 37]. Therefore, our study indicates that gender related difference in LTD may contribute to gender difference in persistent or chronic pain, although we cannot rule out the possible difference in other forms of LTP.