Rapid Estrogenic and Androgenic Neurosteroids Effects in the Induction of Long-Term Synaptic Changes: Implication for Early Memory Formation

“Accordingly, dysfunction of its neuronal networks is implicated in pathological conditions such as depression and post-traumatic stress disorder (Tovote et al., 2015).”

“behavior (Altemus, 2017), and cognition (Luine, 2014), and they are implicated in some psychiatric disorders (Bangasser and Valentino, 2014) modulating the function of different areas of the brain such as the hippocampus, the amygdala, the vestibular and cerebellar systems, and the nucleus striatum (Beauchet, 2006; An…”

“It has been reported that this action is achieved by activation of genomic ERs, most likely the ERα (Gould et al., 1990; Woolley et al., 1990, 1996; Woolley and McEwen, 1993; Murphy and Segal, 1996; Woolley, 1998; Hao et al., 2003; MacLusky et al., 2005).”

“The amygdala is considered a core nucleus of “emotional” memory and for the responses to emotion (Pape and Pare, 2010).”

“Synergic effects consisting of formation of new spines and stabilization of synaptic strength in active mature synapses have in fact been reported to be necessary for long-term synaptic consolidation of neurotransmission (Toni et al., 1999; Yang et al., 2008).”

“Because striatal dopamine (DA) release is critical for LTP induction in this brain structure (Calabresi et al., 2007) and based on the evidence that striatal LTP depends on E2 local synthesis, the interaction between E2 and DA in controlling SPNs’ LTP was explored.”

“behavior (Altemus, 2017), and cognition (Luine, 2014), and they are implicated in some psychiatric disorders (Bangasser and Valentino, 2014) modulating the function of different areas of the brain such as the hippocampus, the amygdala, the vestibular and cerebellar systems, and the nucleus striatum (Beauchet, 2006; An…”

“, 1998; Rudick and Woolley, 2001) and increase NMDAR expression and function (Weiland, 1992; Warren et al., 1995; Gazzaley et al., 1996; Cordoba Montoya and Carrer, 1997; Woolley et al., 1997; Good et al., 1999; Cyr et al., 2000, 2001; Bi et al., 2001; Rudick and Woolley, 2001), ultimately increasing the spine density…”

“P450 aromatase is expressed at hippocampal level and it has been shown that its activation depends on neuronal activity (Kimoto et al., 2001; Hojo et al., 2004, 2008; Balthazart et al., 2006).”

“Sex neurosteroids are a group of cholesterol-derived molecules that are synthesized de novo within the central nervous system (CNS) where they are able to exert local effects (Baulieu, 1981; Baulieu and Robel, 1990).”

“Electrophysiological recordings of hippocampal rat slices evidenced that E2 facilitation of LTP is mediated by NMDAR currents with effects both in males and females (Foy et al., 1999), as confirmed by pharmacological inhibition of the E2- and NMDA-dependent LTP using GluN2B-containing NMDA receptor antagonists (Smith…”

“It has been proposed that LFS-induced LTD is established in the hippocampus via DHT binding to synaptic ARs on delivery of LFS, leading to calcineurin activation and NMDAR suppression, resulting in a decreased presence or dephosphorylation of AMPARs (Hasegawa et al., 2015).”

“It is involved in several plastic phenomena like the visuovestibular calibration (Lisberger and Miles, 1980), the vestibular compensation (Smith and Curthoys, 1989; Dutia, 2010), and the responsiveness to intense stimulation (Massot et al.”

“In fact, it has been shown that the LTP amplitude changes are depending on the estrum phase in the hippocampus (Warren et al., 1995).”

“…emotional Frontiers in Neuroscience | www.frontiersin.org 1 October 2020 | Volume 14 | Article 572511 behavior (Altemus, 2017), and cognition (Luine, 2014), and they are implicated in some psychiatric disorders (Bangasser and Valentino, 2014) modulating the function of different areas of the…”

“In this encephalic structure, the encoding gain increase and decrease adaptation is thought to be mediated by LTP occurring at the parallel fiber–Purkinje cell synapses (PF-LTP) and by LTD (PFLTD) at the same or different synapse subset, respectively (Hansel et al., 2001; Boyden and Raymond, 2003; Boyden et al., 2004;…”

“In this encephalic structure, the encoding gain increase and decrease adaptation is thought to be mediated by LTP occurring at the parallel fiber–Purkinje cell synapses (PF-LTP) and by LTD (PFLTD) at the same or different synapse subset, respectively (Hansel et al., 2001; Boyden and Raymond, 2003; Boyden et al., 2004;…”

“This has been shown to lead to the activation of Ca2+-dependent kinases, P450 aromatase phosphorylation, and subsequent inhibition of E2 synthesis (Balthazart et al., 2001, 2003, 2005; Balthazart and Ball, 2006; Charlier et al., 2015; Fester et al., 2016).”

“It has been reported that this action is achieved by activation of genomic ERs, most likely the ERα (Gould et al., 1990; Woolley et al., 1990, 1996; Woolley and McEwen, 1993; Murphy and Segal, 1996; Woolley, 1998; Hao et al., 2003; MacLusky et al., 2005).”

“, 1998; Rudick and Woolley, 2001) and increase NMDAR expression and function (Weiland, 1992; Warren et al., 1995; Gazzaley et al., 1996; Cordoba Montoya and Carrer, 1997; Woolley et al., 1997; Good et al., 1999; Cyr et al., 2000, 2001; Bi et al., 2001; Rudick and Woolley, 2001), ultimately increasing the spine density…”

“, 1998; Rudick and Woolley, 2001) and increase NMDAR expression and function (Weiland, 1992; Warren et al., 1995; Gazzaley et al., 1996; Cordoba Montoya and Carrer, 1997; Woolley et al., 1997; Good et al., 1999; Cyr et al., 2000, 2001; Bi et al., 2001; Rudick and Woolley, 2001), ultimately increasing the spine density…”

“The influence of E2 on LTP induction was generally observed in the hippocampus of adult male rats; however, different research groups pointed to age-dependent effects, with E2-dependent LTP observed only in young animals (Foy et al., 1999; Bi et al., 2000; Hojo et al., 2008).”

“P450 aromatase is expressed at hippocampal level and it has been shown that its activation depends on neuronal activity (Kimoto et al., 2001; Hojo et al., 2004, 2008; Balthazart et al., 2006).”

“, 1998; Rudick and Woolley, 2001) and increase NMDAR expression and function (Weiland, 1992; Warren et al., 1995; Gazzaley et al., 1996; Cordoba Montoya and Carrer, 1997; Woolley et al., 1997; Good et al., 1999; Cyr et al., 2000, 2001; Bi et al., 2001; Rudick and Woolley, 2001), ultimately increasing the spine density…”

“In this scenario, the induction of LTP of synaptic transmission, involving the increased synthesis or availability of E2 during neuronal activity, might represent the early phase in the process that allows subsequent spine formation and consolidation (Yang et al., 2008; Kato et al., 2013; Dickens et al., 2014).”

“…P450 aromatase, 5α-reductase, LTP, LTD, synaptic plasticity INTRODUCTION Sex neurosteroids are a group of cholesterol-derived molecules that are synthesized de novo within the central nervous system (CNS) where they are able to exert local effects (Baulieu, 1981; Baulieu and Robel, 1990).”

“They also pointed out that E2, synthesized in the CNS, regulates cognition and behavior independently of gender, assigning to the neural E2 signaling system a general modulator role of CNS function (Moradpour et al., 2006; Saldanha et al., 2011; Bailey et al., 2013, 2017; Tuscher et al., 2016; Fester et al., 2017).”

“…neural androgens may also increase spine structure suggesting that the machinery at the basis of synaptic plasticity needs structural improvement either for the induction of the E2-mediated LTP and for the induction of androgenmediated LTD (Leranth et al., 2004; Hatanaka et al., 2009).”

“, 1998; Rudick and Woolley, 2001) and increase NMDAR expression and function (Weiland, 1992; Warren et al., 1995; Gazzaley et al., 1996; Cordoba Montoya and Carrer, 1997; Woolley et al., 1997; Good et al., 1999; Cyr et al., 2000, 2001; Bi et al., 2001; Rudick and Woolley, 2001), ultimately increasing the spine density…”

“…rat slices evidenced that E2 facilitation of LTP is mediated by NMDAR currents with effects both in males and females (Foy et al., 1999), as confirmed by pharmacological inhibition of the E2- and NMDA-dependent LTP using GluN2B-containing NMDA receptor antagonists (Smith and McMahon, 2005, 2006).”

“behavior (Altemus, 2017), and cognition (Luine, 2014), and they are implicated in some psychiatric disorders (Bangasser and Valentino, 2014) modulating the function of different areas of the brain such as the hippocampus, the amygdala, the vestibular and cerebellar systems, and the nucleus striatum (Beauchet, 2006; An…”

“Accordingly, ARs were found to be expressed in the hippocampus at the postsynaptic level (Tabori et al., 2005; Hatanaka et al., 2009), implying that ARs may participate in androgen-induced LTD.”

“…the function of different areas of the brain such as the hippocampus, the amygdala, the vestibular and cerebellar systems, and the nucleus striatum (Beauchet, 2006; Andreescu et al., 2007; Colciago et al., 2015; Bender et al., 2017; Diotel et al., 2018; Mohamad et al., 2018; Wagner et al., 2018;…”

“The cerebellum expresses ERs, ARs, and the synthesizing enzymes for E2 and androgens (Sakamoto et al., 2003; Tsutsui et al., 2011; Hedges et al., 2012).”

“This gender-dependent effect was paralleled by reduction of spine formation (Vierk et al., 2012; Fester and Rune, 2015).”

“P450 aromatase is expressed at hippocampal level and it has been shown that its activation depends on neuronal activity (Kimoto et al., 2001; Hojo et al., 2004, 2008; Balthazart et al., 2006).”

“This has been shown to lead to the activation of Ca2+-dependent kinases, P450 aromatase phosphorylation, and subsequent inhibition of E2 synthesis (Balthazart et al., 2001, 2003, 2005; Balthazart and Ball, 2006; Charlier et al., 2015; Fester et al., 2016).”

“, 1998; Rudick and Woolley, 2001) and increase NMDAR expression and function (Weiland, 1992; Warren et al., 1995; Gazzaley et al., 1996; Cordoba Montoya and Carrer, 1997; Woolley et al., 1997; Good et al., 1999; Cyr et al., 2000, 2001; Bi et al., 2001; Rudick and Woolley, 2001), ultimately increasing the spine density…”

“It is involved in several plastic phenomena like the visuovestibular calibration (Lisberger and Miles, 1980), the vestibular compensation (Smith and Curthoys, 1989; Dutia, 2010), and the responsiveness to intense stimulation (Massot et al., 2012; Pettorossi et al., 2013b).”

“…of their receptors, enhancing the performance on hippocampal memory tasks, as reported in experiments performed with rats and mice (Luine et al., 2003; Aubele et al., 2008; Benice and Raber, 2009; Inagaki et al., 2010, 2012; Babanejad et al., 2012; Phan et al., 2012, 2015; Jacome et al., 2016).”

“Neural E2 exerts an important role in LTP induction in the nucleus striatum with E2 receptors diffusely expressed in the basal ganglia (Creutz and Kritzer, 2004; Krentzel et al., 2019).”

“In this encephalic structure, the encoding gain increase and decrease adaptation is thought to be mediated by LTP occurring at the parallel fiber–Purkinje cell synapses (PF-LTP) and by LTD (PFLTD) at the same or different synapse subset, respectively (Hansel et al., 2001; Boyden and Raymond, 2003; Boyden et al., 2004;…”

“They also pointed out that E2, synthesized in the CNS, regulates cognition and behavior independently of gender, assigning to the neural E2 signaling system a general modulator role of CNS function (Moradpour et al., 2006; Saldanha et al., 2011; Bailey et al., 2013, 2017; Tuscher et al., 2016; Fester et al., 2017).”

“Accordingly, the consolidation of hippocampal memory might be facilitated within minutes after treatments with estrogenic and androgenic neurosteroids or with agonists of their receptors, enhancing the performance on hippocampal memory tasks, as reported in experiments performed with rats and mice (Luine et al., 2003;…”

“It is involved in several plastic phenomena like the visuovestibular calibration (Lisberger and Miles, 1980), the vestibular compensation (Smith and Curthoys, 1989; Dutia, 2010), and the responsiveness to intense stimulation (Massot et al., 2012; Pettorossi et al., 2013b).”

“Enzymes responsible for the biosynthesis of neurosteroids from cholesterol are present in the nervous system (MensahNyagan et al., 1999; Giatti et al., 2019).”

“Together with the sex neurosteroid-mediated bidirectional vestibular synaptic plasticity, the cerebellum participates in the visuo-vestibular calibration of the VOR.”

“Accordingly, LTD amplitude was found to be larger in aged rats than in adults, and interestingly, treatments with E2 was reported to prevent this enhanced LTD in these aged animals but not in adults (Foy, 2001).”

“The role of E2 acting as a neurosteroid in memory formation has been described since the late 1980s and has been recently confirmed by different research groups (Ooishi et al., 2012; Di Mauro et al., 2015; Fester and Rune, 2015; Hasegawa et al., 2015; Lu et al., 2019; Tozzi et al., 2019).”

“…out that E2, synthesized in the CNS, regulates cognition and behavior independently of gender, assigning to the neural E2 signaling system a general modulator role of CNS function (Moradpour et al., 2006; Saldanha et al., 2011; Bailey et al., 2013, 2017; Tuscher et al., 2016; Fester et al., 2017).”

“, 2013) or by changes of the phosphorylation status of P450 aromatase depending on fluctuation of different kinases related to synaptic plasticity (Balthazart and Ball, 2006; Hojo and Kawato, 2018).”

“behavior (Altemus, 2017), and cognition (Luine, 2014), and they are implicated in some psychiatric disorders (Bangasser and Valentino, 2014) modulating the function of different areas of the brain such as the hippocampus, the amygdala, the vestibular and cerebellar systems, and the nucleus striatum (Beauchet, 2006; An…”

“behavior (Altemus, 2017), and cognition (Luine, 2014), and they are implicated in some psychiatric disorders (Bangasser and Valentino, 2014) modulating the function of different areas of the brain such as the hippocampus, the amygdala, the vestibular and cerebellar systems, and the nucleus striatum (Beauchet, 2006; An…”

“…such as the hippocampus, the amygdala, the vestibular and cerebellar systems, and the nucleus striatum (Beauchet, 2006; Andreescu et al., 2007; Colciago et al., 2015; Bender et al., 2017; Diotel et al., 2018; Mohamad et al., 2018; Wagner et al., 2018; Dieni et al., 2020; Luine and Frankfurt, 2020).”

“17β-estradiol is suggested to play a role in synaptic plasticity also in the amygdala, a brain structure where the presence of P450 aromatase has been reported (Zhao et al., 2007; Bender et al., 2017).”

“In this encephalic structure, the encoding gain increase and decrease adaptation is thought to be mediated by LTP occurring at the parallel fiber–Purkinje cell synapses (PF-LTP) and by LTD (PFLTD) at the same or different synapse subset, respectively (Hansel et al., 2001; Boyden and Raymond, 2003; Boyden et al., 2004;…”

“These studies were guided by the major general evidence that inhibition of E2 synthase (P450 aromatase) activity produced hippocampalrelated memory deficits both in women and in female rodents (Bayer et al., 2015; Tuscher et al., 2016).”

“The cerebellum expresses ERs, ARs, and the synthesizing enzymes for E2 and androgens (Sakamoto et al., 2003; Tsutsui et al., 2011; Hedges et al., 2012).”

“Electrophysiological experiments performed in neurons of the dorsal striatum of the male rat showed that E2 synthesis and ER activation are required for the induction of LTP in both spiny projection neurons (SPNs) and cholinergic interneurons because the pharmacological inhibition of P450 aromatase or antagonism of ER…”

“It is well known that testosterone and its more active metabolite DHT attenuate mild cognitive impairment in men, suggesting a role of androgens in sustaining synaptic memory (Hogervorst et al., 2004; Pike et al., 2006; Kang et al., 2014; Pan et al., 2016).”

“This has been shown to lead to the activation of Ca2+-dependent kinases, P450 aromatase phosphorylation, and subsequent inhibition of E2 synthesis (Balthazart et al., 2001, 2003, 2005; Balthazart and Ball, 2006; Charlier et al., 2015; Fester et al., 2016).”

“The role of E2 synthesis on hippocampal LTP was further explored in male rats with experiments inhibiting the P450 aromatase activity (Tanaka and Sokabe, 2012, 2013; Hojo et al., 2015) and more recently by proving that ERα stimulation is able to induce LTP (Clements and Harvey, 2020).”

“behavior (Altemus, 2017), and cognition (Luine, 2014), and they are implicated in some psychiatric disorders (Bangasser and Valentino, 2014) modulating the function of different areas of the brain such as the hippocampus, the amygdala, the vestibular and cerebellar systems, and the nucleus striatum (Beauchet, 2006; An…”

“…only to prevent the induction of LTP but also to unmask LTD of synaptic plasticity, suggesting that the level of neural E2 is a key modulator of MVN neurons’ synaptic plasticity, being able to shift LTP into LTD according to the local availability of this neurosteroid (Grassi et al., 2009, 2010).”

“Different research groups described a relation between changes of intracellular Ca2+ concentrations and P450 aromatase activity, implying the modulation of E2 synthesis (Balthazart et al., 2005; Fester et al., 2016).”

“These findings were also supported by experiments showing a possible facilitatory influence of E2 in the dorsal striatum where DA release has been demonstrated to be potentiated by E2 (Song et al., 2019).”

“These molecules may rapidly change the function of neurons by acting as second messengers leading to the activation of further enzymatic cascades including the src kinase and the MAPK/ERK pathway (Evinger and Levin, 2005; Srivastava, 2012; Murakami et al., 2018).”

“In this scenario, the induction of LTP of synaptic transmission, involving the increased synthesis or availability of E2 during neuronal activity, might represent the early phase in the process that allows subsequent spine formation and consolidation (Yang et al., 2008; Kato et al., 2013; Dickens et al., 2014).”

“Accordingly, the consolidation of hippocampal memory might be facilitated within minutes after treatments with estrogenic and androgenic neurosteroids or with agonists of their receptors, enhancing the performance on hippocampal memory tasks, as reported in experiments performed with rats and mice (Luine et al., 2003;…”

“Depression-like symptoms have been observed in women under treatment with P450 aromatase inhibitors providing evidence of the importance of the E2 signaling system in the amygdala-related physiology (Gallicchio et al., 2012).”

“Scale bars 10 ms; 50 pA. Modified by Tozzi et al. (2019).”

“behavior (Altemus, 2017), and cognition (Luine, 2014), and they are implicated in some psychiatric disorders (Bangasser and Valentino, 2014) modulating the function of different areas of the brain such as the hippocampus, the amygdala, the vestibular and cerebellar systems, and the nucleus striatum (Beauchet, 2006; An…”

“, 2015) and more recently by proving that ERα stimulation is able to induce LTP (Clements and Harvey, 2020).”

“Testosterone is synthesized through conversion of cholesterol into pregnenolone, a neurosteroid that is subsequently metabolized, leading to formation of 5α-dihydrotestosterone (DHT) or 17β-estradiol (E2) by the action of the 5α-reductase or P450 aromatase enzymes, respectively.”

“Different research groups described a relation between changes of intracellular Ca2+ concentrations and P450 aromatase activity, implying the modulation of E2 synthesis (Balthazart et al., 2005; Fester et al., 2016).”

“…of their receptors, enhancing the performance on hippocampal memory tasks, as reported in experiments performed with rats and mice (Luine et al., 2003; Aubele et al., 2008; Benice and Raber, 2009; Inagaki et al., 2010, 2012; Babanejad et al., 2012; Phan et al., 2012, 2015; Jacome et al., 2016).”

“Hippocampal LTD can be elicited by modest Ca2+ inflows entering into neurons via NMDA or metabotropic group I glutamate (mGluI) receptors (Shiroma et al., 2005).”

“Many cellular responses to androgens are transcription independent; in fact, activated ARs are able to associate with molecular substrates in the cytoplasm and the inner layer of the cell membrane to activate intracellular kinase cascades (Soma et al., 2018).”

“…actions, however, were unable to influence LTP in the same brain region and suggest that in the hippocampus, androgens sustain LTD but not LTP induction (Grassi et al., 2011; Grassi et al., 2013; Pettorossi et al., 2013a; Di Mauro et al., 2015; Di Mauro et al., 2017; Tozzi et al., 2019; Figure 1).”

“They also pointed out that E2, synthesized in the CNS, regulates cognition and behavior independently of gender, assigning to the neural E2 signaling system a general modulator role of CNS function (Moradpour et al., 2006; Saldanha et al., 2011; Bailey et al., 2013, 2017; Tuscher et al., 2016; Fester et al., 2017).”

“behavior (Altemus, 2017), and cognition (Luine, 2014), and they are implicated in some psychiatric disorders (Bangasser and Valentino, 2014) modulating the function of different areas of the brain such as the hippocampus, the amygdala, the vestibular and cerebellar systems, and the nucleus striatum (Beauchet, 2006; An…”

“Another mechanism proposed in the literature to explain the neuroprotective properties of progesterone and its metabolites relates to the glutaminergic system since these neurosteroids act as NMDA and AMPA receptors [73].”

“Testosterone and androgen receptor signalling have also been implicated in synaptic formation and plasticity, in the pre-frontal cortex and other areas [48, 49].”

“The rapid effect of sex neurosteroids on long-term synaptic plasticity, including memory formation, requires the maintenance of tonic or phasic local synthesis of steroids controlled by neural activity, but may also depend on circulating hormones, age and sex of the animal [129].”

“A number of studies that have investigated sex steroid effects have shown marked hormone-mediated sex differences in the brain, speci fi cally in the hippocampus (72 – 74).”

“Neurosteroids are also thought to be associated with promoting adult neurogenesis, alongside their other proposed roles of modulating synaptic transmission and neuronal network formation [58].”

“115 In addition, this T metabolite affects plasticity of CA1 hippocampal pyramidal neurons in adolescent male rats, 116 it is necessary for inducing long-term depression of synaptic transmission, 117 and plays a role in the regulation of spine plasticity in circuits related with motivated behaviors.”

“, 2013), neural E2 changes might be related to changes of P450 aromatase depending on fluctuation of kinases related to synaptic plasticity (Hojo, 2018; Tozzi and Bellingacci, 2020).”

“…on GABA receptors (mimicking diazepam pharmacology) (Bitran and Dowd, 1996; Stell et al., 2003), stress mitigation (Young et al., 2001; Lunga and Herbert, 2004), neurotrophic stimulation (Scharfman et al., 2007), and neurosteroid control of hippocampal LTP/depression (Tozzi et al., 2019, 2020).”

“…in LTP induction in different brain regions by exerting rapid, non-genomic effects that are mediated by the activation of its membrane receptors [11,34,39]. that it is able to influence LTP expression in a pathological condition such as synaptic toxicity induced by soluble A β 42 oligomers.”

“Most evidence for the molecular mechanisms of E2 in memory processes comes from the hippocampus, where E2 facilitates induction of long-term potentiation (LTP) and stimulates dendritic spine formation and remodeling; however, other regions may be similarly impacted [24].”

“53,149 The addition of sulfate to estrogen and other placentally produced hormones, also known as sulfonation, is a process involved in fetal brain development.”

“Androgen receptor signaling is implicated in synapse formation and neuronal plasticity in regions such as the prefrontal cortex [282].”

“56 Thus, while the hippocampal functions of androgens and estrogens do not necessarily require peripheral supply of the respective hormones, 57 – 59 various ways exist how these functions can be adapted to acute organismic requirements, which differ between males and females throughout life (e.g.,…”

“Previous studies used E2 to investigate how estrogen rapidly regulates neuronal activities (Smejkalova andWoolley, 2010; Krentzel et al., 2018; Tozzi et al., 2020).”