Estrogen alters hippocampal dendritic spine shape and enhances synaptic protein immunoreactivity and spatial memory in female mice

doi:10.1073/pnas.0307313101

Estrogen alters hippocampal dendritic spine shape and enhances synaptic protein immunoreactivity and spatial memory in female mice

^*Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021; ^‡Department of Psychology, University of California, Santa Barbara, CA 93106; Laboratories of ^§Neuroendocrinology and ^**Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021; ^¶Department of Psychology, Hunter College, 695 Park Avenue, New York, NY 10021; and ^∥Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508

Contributed by Bruce S. McEwen, December 23, 2003

Abstract

Estrogen (E) treatment induces axospinous synapses in rat hippocampus in vivo and in cultured hippocampal neurons in vitro. To better explore the molecular mechanisms underlying this phenomenon, we have established a mouse model for E action in the hippocampus by using Golgi impregnation to examine hippocampal dendritic spine morphology, radioimmunocytochemistry (RICC) and silver-enhanced immunocytochemistry to examine expression levels of synaptic protein markers, and hippocampal-dependent object-placement memory as a behavioral readout for the actions of E. In ovariectomized mice of several strains and F₁ hybrids, the total dendritic spine density on neurons in the CA1 region was not enhanced by E treatment, a finding that differs from that in the female rat. E treatment of ovariectomized C57BL/6J mice, however, caused an increase in the number of spines with mushroom shapes. By RICC and silver-enhanced immunocytochemistry, we found that the immunoreactivity of postsynaptic markers (PSD95 and spinophilin) and a presynaptic marker (syntaxin) were enhanced by E treatment throughout all fields of the dorsal hippocampus. In the object-placement tests, E treatment enhanced performance of object placement, a spatial episodic memory task. Taken together, the morphology and RICC results suggest a previously uncharacterized role of E in synaptic structural plasticity that may be interpreted as a facilitation of the spine-maturation process and may be associated with enhancement of hippocampal-dependent memory.

Footnotes

↵ † To whom correspondence may be addressed. E-mail: chl2011{at}med.cornell.edu or mcewen{at}rockefeller.edu.
Abbreviations: E, estrogen; EB, 17β-estradiol benzoate; IR, immunoreactivity; NMDA, N-methyl-d-aspartate; OVX, ovariectomized; RICC, radioimmunocytochemistry; RT, room temperature; SEI, silver-enhanced immunocytochemistry.