TY - JOUR
T1 - Neuron‐derived estrogen—a key neuromodulator in synaptic function and memory
AU - Brann, Darrell W.
AU - Lu, Yujiao
AU - Wang, Jing
AU - Sareddy, Gangadhara R.
AU - Pratap, Uday P.
AU - Zhang, Quanguang
AU - Tekmal, Rajeshwar R.
AU - Vadlamudi, Ratna K.
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - In addition to being a steroid hormone, 17b‐estradiol (E2) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans. Neuron‐derived E2 (NDE2) is synthesized from androgen precursors via the action of the biosynthetic enzyme aroma-tase, which is located at synapses and in presynaptic terminals in neurons in both the male and female brain. In this review, we discuss evidence supporting a key role for NDE2 as a neuromodu-lator that regulates synaptic plasticity and memory. Evidence supporting an important neuromod-ulatory role of NDE2 in the brain has come from studies using aromatase inhibitors, aromatase over-expression in neurons, global aromatase knockout mice, and the recent development of conditional forebrain neuron‐specific knockout mice. Collectively, these studies demonstrate a key role of NDE2 in the regulation of synapse and spine density, efficacy of excitatory synaptic transmission and long-term potentiation, and regulation of hippocampal‐dependent recognition memory, spatial reference memory, and contextual fear memory. NDE2 is suggested to achieve these effects through estrogen receptor‐mediated regulation of rapid kinase signaling and CREB‐BDNF signaling pathways, which regulate actin remodeling, as well as transcription, translation, and transport of synaptic proteins critical for synaptic plasticity and function.
AB - In addition to being a steroid hormone, 17b‐estradiol (E2) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans. Neuron‐derived E2 (NDE2) is synthesized from androgen precursors via the action of the biosynthetic enzyme aroma-tase, which is located at synapses and in presynaptic terminals in neurons in both the male and female brain. In this review, we discuss evidence supporting a key role for NDE2 as a neuromodu-lator that regulates synaptic plasticity and memory. Evidence supporting an important neuromod-ulatory role of NDE2 in the brain has come from studies using aromatase inhibitors, aromatase over-expression in neurons, global aromatase knockout mice, and the recent development of conditional forebrain neuron‐specific knockout mice. Collectively, these studies demonstrate a key role of NDE2 in the regulation of synapse and spine density, efficacy of excitatory synaptic transmission and long-term potentiation, and regulation of hippocampal‐dependent recognition memory, spatial reference memory, and contextual fear memory. NDE2 is suggested to achieve these effects through estrogen receptor‐mediated regulation of rapid kinase signaling and CREB‐BDNF signaling pathways, which regulate actin remodeling, as well as transcription, translation, and transport of synaptic proteins critical for synaptic plasticity and function.
KW - Aromatase
KW - Cognition
KW - Estradiol
KW - Memory
KW - Neuroestrogen
KW - Neuromodulator
KW - Neurosteroid
KW - Steroid hormone
KW - Synapse
UR - http://www.scopus.com/inward/record.url?scp=85120670793&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120670793&partnerID=8YFLogxK
U2 - 10.3390/ijms222413242
DO - 10.3390/ijms222413242
M3 - Review article
C2 - 34948039
AN - SCOPUS:85120670793
SN - 1661-6596
VL - 22
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 24
M1 - 13242
ER -