TY - JOUR
T1 - Ovarian hormone deficiency reduces intrinsic excitability and abolishes acute estrogen sensitivity in hippocampal CA1 pyramidal neurons
AU - Wu, Wendy W.
AU - Adelman, John P.
AU - Maylie, James
PY - 2011/2/16
Y1 - 2011/2/16
N2 - Premature and uncompensated loss of ovarian hormones following ovariectomy (OVX) elevates the risks of cognitive impairment and dementia. These risks are prevented with estrogen (E2)-containing hormone replacement therapy initiated shortly following OVX but not after substantial delay. Currently, the cellular bases underlying these clinical findings are unknown. At the cellular level, intrinsic membrane properties regulate the efficiency of synaptic inputs to initiate output action potentials (APs), thereby affecting neuronal communication, hence cognitive processing. This study tested the hypothesis that in CA1 pyramidal neurons, intrinsic membrane properties and their acute regulation by E2 require ovarian hormones for maintenance. Whole-cell current-clamp recordings were performed on neurons from ∼7-month-old OVX rats that experienced either short-term (10 d, control OVX) or long-term (5 months, OVXLT) ovarian hormone deficiency. The results reveal that long-term hormone deficiency reduced intrinsic membrane excitability (IE) as measured by the number of evoked APs and firing duration for a given current injection. This was accompanied by AP broadening, an increased slow afterhyperpolarization (sAHP), and faster accumulation of NaV channel inactivation during repetitive firing. In the control OVX neurons, E 2 acutely increased IE and reduced the sAHP. In contrast, acute regulation of IE by E2 was absent in the OVXLT neurons. Since the degree of IE of hippocampal pyramidal neurons is positively related with hippocampus-dependent learning ability, and modulation of IE is observed following successful learning, these findings provide a framework for understanding hormone deficiency-related cognitive impairment and the critical window for therapy initiation.
AB - Premature and uncompensated loss of ovarian hormones following ovariectomy (OVX) elevates the risks of cognitive impairment and dementia. These risks are prevented with estrogen (E2)-containing hormone replacement therapy initiated shortly following OVX but not after substantial delay. Currently, the cellular bases underlying these clinical findings are unknown. At the cellular level, intrinsic membrane properties regulate the efficiency of synaptic inputs to initiate output action potentials (APs), thereby affecting neuronal communication, hence cognitive processing. This study tested the hypothesis that in CA1 pyramidal neurons, intrinsic membrane properties and their acute regulation by E2 require ovarian hormones for maintenance. Whole-cell current-clamp recordings were performed on neurons from ∼7-month-old OVX rats that experienced either short-term (10 d, control OVX) or long-term (5 months, OVXLT) ovarian hormone deficiency. The results reveal that long-term hormone deficiency reduced intrinsic membrane excitability (IE) as measured by the number of evoked APs and firing duration for a given current injection. This was accompanied by AP broadening, an increased slow afterhyperpolarization (sAHP), and faster accumulation of NaV channel inactivation during repetitive firing. In the control OVX neurons, E 2 acutely increased IE and reduced the sAHP. In contrast, acute regulation of IE by E2 was absent in the OVXLT neurons. Since the degree of IE of hippocampal pyramidal neurons is positively related with hippocampus-dependent learning ability, and modulation of IE is observed following successful learning, these findings provide a framework for understanding hormone deficiency-related cognitive impairment and the critical window for therapy initiation.
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U2 - 10.1523/JNEUROSCI.6081-10.2011
DO - 10.1523/JNEUROSCI.6081-10.2011
M3 - Article
C2 - 21325532
AN - SCOPUS:79951835437
SN - 0270-6474
VL - 31
SP - 2638
EP - 2648
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 7
ER -