Objective To study the effect and mechanism of estradiol (E2) regulating sortilin-related receptor A (SorLA) expression on hippocampal spine density and synaptic protein expression of mouse.   Methods Thirty-two C57BL/6 female mice were randomly divided into sham group, ovariectomized(OVX) group, OVX+E2 group, and OVX+fulvestrant(Fu)+E2 group; The SorLA expression in hippocampal CA1 region of mouse was detected by Western blotting and immunohistochemical staining. Forty C57BL/6 female mice were randomly divided into sham+NC-sgRNA group, OVX+NC-sgRNA group, OVX+NC-sgRNA+E2 group, and OVX+sortilin-related receptor 1(Sorl1)-sgRNA+E2; the spine density in hippocampal CA1 region was detected by Golgi-Cox staining and the postsynaptic density protein 95 (PSD-95) and synapsin-1 (SYN1) expression in hippocampal CA1 region were detected by Western blotting and immunohistochemical staining.   Results Compared with the sham group, the SorLA expression in OVX group and OVX+Fu+E2 group decreased significantly (P<0.05), but OVX+E2group had no significant difference (P>0.05). Compared with the sham+NC-sgRNA group, the density of dendritic spines, and the PSD-95, SYN1 expression of OVX+NC-sgRNA group and OVX+Sorl1-sgRNA+E2 group decreased significantly (P<0.05), but OVX+NC-sgRNA+E2 group had no significant difference (P>0-05).   Conclusion E2 may upregulate SorLA expression through estrogen receptor and then promote the hippocampal spine density and synaptic protein expression of mouse.