TY - JOUR
T1 - Estrogen regulation of spine density and excitatory synapses in rat prefrontal and somatosensory cerebral cortex
AU - Khan, Mohammad M.
AU - Dhandapani, Krishnan Michael
AU - Zhang, Quanguang
AU - Brann, Darrell W
N1 - Funding Information:
This research was supported by a Research Grant ( NS050730 ) from the National Institutes of Neurological Disorders and Stroke , National Institutes of Health .
PY - 2013/6
Y1 - 2013/6
N2 - The steroid hormone, 17β-estradiol (E2) has been reported to enhance executive functions that are known to be mediated by the prefrontal cortex (PFC), although the underlying mechanisms remain unclear. To shed light on the potential mechanisms, we examined the effect of E2 in vivo upon spine density in the rat PFC and the somatosensory cortex (SSC), which has been implicated to be a transient storage site for information that can also contribute to working memory. The results revealed that E2 significantly enhanced the number of dendritic spines in both the SSC and PFC, as well as the expression of spinophilin. In vitro studies revealed further mechanistic insights by demonstrating that E2 enhanced AMPA GluR1 receptor expression and excitatory glutamatergic synapse formation in rat cortical neurons, without an effect upon inhibitory GABAergic synapse formation. Furthermore, E2 rapidly enhanced ERK and Akt activation in cortical neurons, and inhibitors of ERK and Akt activation significantly attenuated E2 induction of excitatory glutamatergic synapses. Administration of E2-BSA likewise significantly enhanced excitatory glutamatergic synapses in cortical neurons, and administration of an ER antagonist, ICI182,780 and a non-NMDA receptor antagonist (NBQX) significantly attenuated the effect of E2 upon enhancement of excitatory glutamatergic synapses, suggesting mediation by extranuclear estrogen receptors and involvement of non-NMDA receptor activation and signaling. As a whole, the studies demonstrate that E2 enhances spine density in both the PFC and SSC, and that E2 enhances excitatory glutamatergic synapse formation in cortical neurons via a rapid extranuclear ER-mediated signaling mechanism that involves up-regulation of GluR1 and mediation by Akt and ERK signaling pathways.
AB - The steroid hormone, 17β-estradiol (E2) has been reported to enhance executive functions that are known to be mediated by the prefrontal cortex (PFC), although the underlying mechanisms remain unclear. To shed light on the potential mechanisms, we examined the effect of E2 in vivo upon spine density in the rat PFC and the somatosensory cortex (SSC), which has been implicated to be a transient storage site for information that can also contribute to working memory. The results revealed that E2 significantly enhanced the number of dendritic spines in both the SSC and PFC, as well as the expression of spinophilin. In vitro studies revealed further mechanistic insights by demonstrating that E2 enhanced AMPA GluR1 receptor expression and excitatory glutamatergic synapse formation in rat cortical neurons, without an effect upon inhibitory GABAergic synapse formation. Furthermore, E2 rapidly enhanced ERK and Akt activation in cortical neurons, and inhibitors of ERK and Akt activation significantly attenuated E2 induction of excitatory glutamatergic synapses. Administration of E2-BSA likewise significantly enhanced excitatory glutamatergic synapses in cortical neurons, and administration of an ER antagonist, ICI182,780 and a non-NMDA receptor antagonist (NBQX) significantly attenuated the effect of E2 upon enhancement of excitatory glutamatergic synapses, suggesting mediation by extranuclear estrogen receptors and involvement of non-NMDA receptor activation and signaling. As a whole, the studies demonstrate that E2 enhances spine density in both the PFC and SSC, and that E2 enhances excitatory glutamatergic synapse formation in cortical neurons via a rapid extranuclear ER-mediated signaling mechanism that involves up-regulation of GluR1 and mediation by Akt and ERK signaling pathways.
KW - Estradiol
KW - Kinase
KW - Nongenomic
KW - Synapse
KW - Synaptic plasticity
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U2 - 10.1016/j.steroids.2012.12.005
DO - 10.1016/j.steroids.2012.12.005
M3 - Article
C2 - 23276632
AN - SCOPUS:84876675798
SN - 0039-128X
VL - 78
SP - 614
EP - 623
JO - Steroids
JF - Steroids
IS - 6
ER -