Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons

The ovarian steroids exert both long-term and short-term actions on neurons involving different cellular mechanisms. We have investigated the long-term and short-term effects of estrogen on the electrophysiological properties of CA1 neurons utilizing intracellular recordings in hippocampal slices prepared from ovariectomized female rats. An in vivo estrogen-priming paradigm was used to examine long-term genomic actions of estrogen. Subcutaneous estrogen injections 2 d prior to recording had no effect on the intrinsic membrane properties of CA1 neurons, but increased synaptic excitability by prolonging the EPSP and inducing repetitive firing in response to Schaffer collateral stimulation. Short-term effects of estrogen that presumedly involve direct membrane interactions were tested by application of steroids directly to the slice. Superfusion of 17β-estradiol, but not 17α-estradiol, caused a rapid and reversible increase in the amplitude of the Schaffer collateral-activated EPSP. This potentiation of the EPSP by 17β-estradiol still occurred in the presence of the NMDA antagonist 2-amino-5-phosphonovalerate, but was blocked by the non-NMDA antagonist 6- cyano-7-nitroquinoxaline-2,3-dione. Depolarizing responses to iontophoretic pulses of exogenous glutamate were also potentiated by 17β-estradiol, suggesting a postsynaptic site of action. In addition, 17β-estradiol potentiated the responses to α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, kainate, and quisqualate, but not NMDA, further implicating non-NMDA receptors in the short-term action of estrogen. In contrast, 17β-estradiol had no effect on responses to exogenous GABA or on the Schaffer collateral- induced late IPSP. These findings indicate that synaptic functioning and neuronal excitability in the hippocampus are subject to both long-term and short-term excitatory modulation by estrogen.