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Cited by 97Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsAlzheimer's disease research and treatments

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Neurosteroid Actions in Memory and Neurologic/Neuropsychiatric Disorders

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Ratner, Marcia H., Kumaresan, Vidhya, Farb, David H.·2019·Frontiers in Endocrinology
DOI 10.3389/fendo.2019.00169PMC PMC6465949
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Abstract

Memory dysfunction is a symptomatic feature of many neurologic and neuropsychiatric disorders; however, the basic underlying mechanisms of memory and altered states of circuitry function associated with disorders of memory remain a vast unexplored territory. The initial discovery of endogenous neurosteroids triggered a quest to elucidate their role as neuromodulators in normal and diseased brain function. In this review, based on the perspective of our own research, the advances leading to the discovery of positive and negative neurosteroid allosteric modulators of GABA type-A (GABAA), NMDA, and non-NMDA type glutamate receptors are brought together in a historical and conceptual framework. We extend the analysis toward a state-of-the art view of how neurosteroid modulation of neural circuitry function may affect memory and memory deficits. By aggregating the results from multiple laboratories using both animal models for disease and human clinical research on neuropsychiatric and age-related neurodegenerative disorders, elements of a circuitry level view begins to emerge. Lastly, the effects of both endogenously active and exogenously administered neurosteroids on neural networks across the life span of women and men point to a possible underlying pharmacological connectome by which these neuromodulators might act to modulate memory across diverse altered states of mind.

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Figures

Figure 1 Progesterone and PregS differentially modulate whole cell currents induced by GABA, glycine and NMDA. Progesterone (P) (100 μM) potentiates the GABA response (A) and inhibits the glycine (B) response. (C) Dose response curves for progesterone modulation of GABA and glycine currents; enhancement of the GABA response by progesterone occurs over the same concentration range as inhibition of the glycine response. (D) PregS (100 μM) potentiates the NMDA response (normal media [Gly]). (E) PregS and glycine potentiate NMDA response by different mechanisms. (F) In the presence of the maximal concentration (10 μM) of glycine, PregS (100 μM) enhances (179 ± 17.1%; n = 4) the response induced by 30 μM of NMDA; (F) In the presence of near maximal concentration of PregS (100 μM), glycine (10 μM) reversibly potentiates (210 ± 36.5%; n = 4) the NMDA response. (G) Dose response curves for PregS modulation of NMDA and GABA currents. Enhancement of the NMDA response by PregS occurs over the same concentration range as inhibition of the GABA response (Horizontal bar above each trace represents period of drug application) [Modified from Wu et al. (23, 24) with Permission].
Figure 1 Progesterone and PregS differentially modulate whole cell currents induced by GABA, glycine and NMDA. Progesterone (P) (100 μM) potentiates the GABA response (A) and inhibits the glycine (B) response. (C) Dose response curves for progesterone modulation of GABA and glycine currents; enhancement of the GABA response by progesterone occurs over the same concentration range as inhibition of the glycine response. (D) PregS (100 μM) potentiates the NMDA response (normal media [Gly]). (E) PregS and glycine potentiate NMDA response by different mechanisms. (F) In the presence of the maximal concentration (10 μM) of glycine, PregS (100 μM) enhances (179 ± 17.1%; n = 4) the response induced by 30 μM of NMDA; (F) In the presence of near maximal concentration of PregS (100 μM), glycine (10 μM) reversibly potentiates (210 ± 36.5%; n = 4) the NMDA response. (G) Dose response curves for PregS modulation of NMDA and GABA currents. Enhancement of the NMDA response by PregS occurs over the same concentration range as inhibition of the GABA response (Horizontal bar above each trace represents period of drug application) [Modified from Wu et al. (23, 24) with Permission].CC BY · PubMed Central
Figure 2 Delayed-onset potentiation of NMDARs is induced by PregS. Two-electrode whole-cell voltage clamp recording from Xenopus oocytes expressing NR1/2A subunits following application of PregS (100 μM) and NMDA (300 μM). (A) Potentiation of the NMDA response by PregS. Black bars indicate successive applications of NMDA. (B) Peak NMDA-induced currents determined as in (A) are normalized to the average response before application of PregS beginning at t = 0. Smooth curve reflects an exponential fit (t = 184 s). Error bars indicate S.E.M. (n = 3). Arrows indicate rapid and delayed components of potentiation. (D) In oocytes expressing NR1/2A receptors, delayed potentiation but not rapid potentiation is induced by 100 nM PregS. (D) Averaged values of normalized peak current responses for rapid and delayed increase. When added simultaneously with NMDA, PregS produces a negligible potentiation of the NMDA response (1 ± 2%), whereas after 10 min pre-incubation with 100 nM PregS, the response to NMDA was enhanced by 45 ± 3%. Error bars represent S.E.M (n = 8–10). *Indicates a significant difference between rapid and delayed potentiation (P < 0.0005). (E) Cartoon shows NMDA and 9-aminoacridine (9-AA) (100 μM) co-applied to Xenopus oocytes expressing NR1/2A receptors results in a transient inward current as NMDA-activated channels are blocked by 9-AA (a voltage-dependent open-channel blocker). As the holding potential is switched from −70 to +70 mV, an outward tail current reflecting 9-AA unblock of NMDAR channels ensues (black traces). Cells were then exposed to vehicle (Ba-Ringer) (F) or PregS (G) for 10 min, and the 9-AA block and unblock sequences were repeated (blue traces). Peak tail currents after baseline subtraction are expressed relative to the control current (black trace) from the same cell (p2/p1). (H) The peak current ratio p2/p1 for PregS-treated oocytes (blue bar; n = 8) is significantly higher than for vehicle-treated oocytes (white bar; n = 6). *Relative current P < 0.00001, unpaired 2-tail t-test [From Kostakis et al. (47) with Permission].
Figure 2 Delayed-onset potentiation of NMDARs is induced by PregS. Two-electrode whole-cell voltage clamp recording from Xenopus oocytes expressing NR1/2A subunits following application of PregS (100 μM) and NMDA (300 μM). (A) Potentiation of the NMDA response by PregS. Black bars indicate successive applications of NMDA. (B) Peak NMDA-induced currents determined as in (A) are normalized to the average response before application of PregS beginning at t = 0. Smooth curve reflects an exponential fit (t = 184 s). Error bars indicate S.E.M. (n = 3). Arrows indicate rapid and delayed components of potentiation. (D) In oocytes expressing NR1/2A receptors, delayed potentiation but not rapid potentiation is induced by 100 nM PregS. (D) Averaged values of normalized peak current responses for rapid and delayed increase. When added simultaneously with NMDA, PregS produces a negligible potentiation of the NMDA response (1 ± 2%), whereas after 10 min pre-incubation with 100 nM PregS, the response to NMDA was enhanced by 45 ± 3%. Error bars represent S.E.M (n = 8–10). *Indicates a significant difference between rapid and delayed potentiation (P < 0.0005). (E) Cartoon shows NMDA and 9-aminoacridine (9-AA) (100 μM) co-applied to Xenopus oocytes expressing NR1/2A receptors results in a transient inward current as NMDA-activated channels are blocked by 9-AA (a voltage-dependent open-channel blocker). As the holding potential is switched from −70 to +70 mV, an outward tail current reflecting 9-AA unblock of NMDAR channels ensues (black traces). Cells were then exposed to vehicle (Ba-Ringer) (F) or PregS (G) for 10 min, and the 9-AA block and unblock sequences were repeated (blue traces). Peak tail currents after baseline subtraction are expressed relative to the control current (black trace) from the same cell (p2/p1). (H) The peak current ratio p2/p1 for PregS-treated oocytes (blue bar; n = 8) is significantly higher than for vehicle-treated oocytes (white bar; n = 6). *Relative current P < 0.00001, unpaired 2-tail t-test [From Kostakis et al. (47) with Permission].CC BY · PubMed Central
Figure 3 Steroid modulatory domain of NMDARs. (A) (Left) Schematic representation of wildtype NR2B, NR2D, and the NR2B, NR2D chimeras. The contribution of NR2B and NR2D to chimeras is depicted in black and white, respectively. The scales at the top indicate the residue numbers in the wildtype subunits at junctions. Vertical bars represent the four hydrophobic membrane domains. (Right) Percent increase in the NMDA glycine response (elicited by 300 μM NMDA and 50 μM glycine in oocytes expressing NR1-1a and NR2 subunits) in the presence of 100 μM PS is indicated. Error bars are SEMs. Numbers adjacent to the error bars indicate the number of oocytes used in the study. (B) Concentration–response curves of PregS modulation for receptors containing NR2B (○), NR2D (Δ), χ4 (), and χ5 (♢), were determined in the presence of saturating concentrations of NMDA (300 μM) and glycine (50 μM). The EC50 (NMDA) for NR1-1a χ4 and NR1-1a_NR2B are both 22 ± 1 μM, and EC50 (glycine) is 0.30 ± 0.02 and 0.10 ± 0.02 μM, respectively. (C) The topological representation of the NR2B subunit and the location of the identified segment are depicted in red. Membrane domains are denoted as M1–M4. The amino terminus (N) is located on the extracellular side and the carboxyl terminus (C) on the intracellular side of the plasma membrane. (D) Molecular modeling of potential binding pocket for PregS. The dimer comprising the S1/S2 domains of NR2B and NR1-1a is depicted in a 3D ribbon structure with helices colored in blue and sheets colored in yellow with PregS docked at the interface between the two subunits. Our finding that both J and K helices (see arrows) and M4 of the NR2B subunit are required to confer PS potentiation indicates that M4 is also critical in coupling allosteric modulation from extracellular binding regions to the gating mechanism. (E) Detailed view of the potential binding pocket for PregS on NR2B. (F) Detailed view of the potential binding pocket for PregS on NR1-1a. NR1-1a or NR2B have been removed from the models to show the hydrophobic pocket on NR2B (E) or NR1-1a (F), respectively. The receptor surface is colored according to a hydrophobicity scale with hydrophobic residues in red and charged residues in blue. PregS is depicted in a stick configuration and colored by the atom type with hydrogen in white, carbon in green, oxygen in red, and sulfur in yellow. Our finding that both J and K helices (see arrows) and M4 of the NR2B subunit are required to confer PS potentiation indicates that M4 is also critical in coupling allosteric modulation from extracellular binding regions to the gating mechanism [From Jang et al. (43) with Permission].
Figure 3 Steroid modulatory domain of NMDARs. (A) (Left) Schematic representation of wildtype NR2B, NR2D, and the NR2B, NR2D chimeras. The contribution of NR2B and NR2D to chimeras is depicted in black and white, respectively. The scales at the top indicate the residue numbers in the wildtype subunits at junctions. Vertical bars represent the four hydrophobic membrane domains. (Right) Percent increase in the NMDA glycine response (elicited by 300 μM NMDA and 50 μM glycine in oocytes expressing NR1-1a and NR2 subunits) in the presence of 100 μM PS is indicated. Error bars are SEMs. Numbers adjacent to the error bars indicate the number of oocytes used in the study. (B) Concentration–response curves of PregS modulation for receptors containing NR2B (○), NR2D (Δ), χ4 (), and χ5 (♢), were determined in the presence of saturating concentrations of NMDA (300 μM) and glycine (50 μM). The EC50 (NMDA) for NR1-1a χ4 and NR1-1a_NR2B are both 22 ± 1 μM, and EC50 (glycine) is 0.30 ± 0.02 and 0.10 ± 0.02 μM, respectively. (C) The topological representation of the NR2B subunit and the location of the identified segment are depicted in red. Membrane domains are denoted as M1–M4. The amino terminus (N) is located on the extracellular side and the carboxyl terminus (C) on the intracellular side of the plasma membrane. (D) Molecular modeling of potential binding pocket for PregS. The dimer comprising the S1/S2 domains of NR2B and NR1-1a is depicted in a 3D ribbon structure with helices colored in blue and sheets colored in yellow with PregS docked at the interface between the two subunits. Our finding that both J and K helices (see arrows) and M4 of the NR2B subunit are required to confer PS potentiation indicates that M4 is also critical in coupling allosteric modulation from extracellular binding regions to the gating mechanism. (E) Detailed view of the potential binding pocket for PregS on NR2B. (F) Detailed view of the potential binding pocket for PregS on NR1-1a. NR1-1a or NR2B have been removed from the models to show the hydrophobic pocket on NR2B (E) or NR1-1a (F), respectively. The receptor surface is colored according to a hydrophobicity scale with hydrophobic residues in red and charged residues in blue. PregS is depicted in a stick configuration and colored by the atom type with hydrogen in white, carbon in green, oxygen in red, and sulfur in yellow. Our finding that both J and K helices (see arrows) and M4 of the NR2B subunit are required to confer PS potentiation indicates that M4 is also critical in coupling allosteric modulation from extracellular binding regions to the gating mechanism [From Jang et al. (43) with Permission].CC BY · PubMed Central
Figure 4 Activation of GABAARs by neurosteroids, such as ALLO and THDOC depends on occupancy of both the activation and potentiation sites on the transmembrane domain. (A) Regulation of GABAAR, is dependent on the C3a hydroxyl group on the A-ring and the C20 ketone on the D-ring shown here in structures of ALLO and THDOC. (B) Neurosteroid activity is determined by α-subunit M1 domain residues. Replacement of membrane domains M1 through to the end of M2 in the murine α1 and β2 subunits with the corresponding sequence from the RDL subunit, forming the chimeras αR and βR, respectively, was the first modification used to established their GABAAR pharmacology. Potentiation and direct activation of GABAARs by THDOC and ALLO was abolished in chimeric receptors incorporating αR; receptors containing βR were indistinguishable from the wild type. Polar residues in α1 (blue) are in bold, with Thr 236 and Gln 241 (red) highlighted. The transmembrane domains are boxed. (C) Neurosteroid potentiation requires α-subunit M1 and M4 membrane domains. Ribbon structure of α subunit viewed from the lipid bilayer showing αGln 241, αAsn 407, and αTyr 410 docking with a THDOC molecule. The channel lining the M2 membrane domain is shown in purple (a section of M3 domain is omitted for clarity). (D) Neurosteroid activation binding site spans the β/α-subunit interface. View of transmembrane region (extracellular and cytoplasmic domains removed) with a bound THDOC molecule. Replacing αThr 236 with non-hydrogen-bonding isoleucine or valine reduces the agonist potency of ALLO and THDOC. (E) Neurosteroid potentiation requires α-subunit M1 and M4 membrane domains. Homology model of THDOC bound to the potentiation site between M1 and M4 membrane domains of the [David: should the following show alpha or beta symbol?] α subunit (M3 membrane domain removed from figure for clarity). Ile 238 is predicted to lie close to the A-ring of THDOC (left). Introduction of a similar-sized but polar side chain at residue 238, such as replacement with asparagine repels the steroid (right). (F) Replacement of Cys 233 (left) with tryptophan (right) increases the steric hindrance for THDOC binding to βTyr 284 and αThr 236 [From Figures 1, 3, 4 of Hosie et al. (109)].
Figure 4 Activation of GABAARs by neurosteroids, such as ALLO and THDOC depends on occupancy of both the activation and potentiation sites on the transmembrane domain. (A) Regulation of GABAAR, is dependent on the C3a hydroxyl group on the A-ring and the C20 ketone on the D-ring shown here in structures of ALLO and THDOC. (B) Neurosteroid activity is determined by α-subunit M1 domain residues. Replacement of membrane domains M1 through to the end of M2 in the murine α1 and β2 subunits with the corresponding sequence from the RDL subunit, forming the chimeras αR and βR, respectively, was the first modification used to established their GABAAR pharmacology. Potentiation and direct activation of GABAARs by THDOC and ALLO was abolished in chimeric receptors incorporating αR; receptors containing βR were indistinguishable from the wild type. Polar residues in α1 (blue) are in bold, with Thr 236 and Gln 241 (red) highlighted. The transmembrane domains are boxed. (C) Neurosteroid potentiation requires α-subunit M1 and M4 membrane domains. Ribbon structure of α subunit viewed from the lipid bilayer showing αGln 241, αAsn 407, and αTyr 410 docking with a THDOC molecule. The channel lining the M2 membrane domain is shown in purple (a section of M3 domain is omitted for clarity). (D) Neurosteroid activation binding site spans the β/α-subunit interface. View of transmembrane region (extracellular and cytoplasmic domains removed) with a bound THDOC molecule. Replacing αThr 236 with non-hydrogen-bonding isoleucine or valine reduces the agonist potency of ALLO and THDOC. (E) Neurosteroid potentiation requires α-subunit M1 and M4 membrane domains. Homology model of THDOC bound to the potentiation site between M1 and M4 membrane domains of the [David: should the following show alpha or beta symbol?] α subunit (M3 membrane domain removed from figure for clarity). Ile 238 is predicted to lie close to the A-ring of THDOC (left). Introduction of a similar-sized but polar side chain at residue 238, such as replacement with asparagine repels the steroid (right). (F) Replacement of Cys 233 (left) with tryptophan (right) increases the steric hindrance for THDOC binding to βTyr 284 and αThr 236 [From Figures 1, 3, 4 of Hosie et al. (109)].CC BY · PubMed Central
Figure 5 Docking positions of ALLO and photolabeling reagents in the intersubunit and intrasubunit sites. (A) Intersubunit docking sites; the photolabeled residues for Glu-272 (5α-6-AziP, 5α-12-AziP, 5α-15-AziP) and Phe-267 (KK200), are shown as purple spheres. (B) The intrasubunit docking sites; the photolabeled residues, Tyr-194 (5α-6-AziP) and Asn-307 (KK200), are shown as purple spheres [From Cheng et al. (134), with Permission].
Figure 5 Docking positions of ALLO and photolabeling reagents in the intersubunit and intrasubunit sites. (A) Intersubunit docking sites; the photolabeled residues for Glu-272 (5α-6-AziP, 5α-12-AziP, 5α-15-AziP) and Phe-267 (KK200), are shown as purple spheres. (B) The intrasubunit docking sites; the photolabeled residues, Tyr-194 (5α-6-AziP) and Asn-307 (KK200), are shown as purple spheres [From Cheng et al. (134), with Permission].CC BY · PubMed Central
Figure 6 PregS activates silent synapses. (A) Sample traces of whole-cell patch-clamp recording from CA1 pyramidal neurons in hippocampal slices from a P3 rat reveal mEPSCs after 25 μM PregS exposure. This effect, which is absent under control conditions, is not reversed by washout. (B) Depiction of the time course for the recordings shown in figure (A). Note that NBQX blocks this effect, indicating it is mediated by AMPA receptors. (C) Cumulative probability plot. The distribution of the mEPSC inter-event intervals at 10 vs. 25 min is not influenced by PregS exposure. Average mEPSC traces illustrating the lack of an effect of PregS on mEPSC amplitude at these time points. (D) Summary figure showing effects of vehicle (DMSO) and PregS (application represented by the gray bar) on the number of events as a function of time (n = 8–12) [From Valenzuela et al. (156) with Permission].
Figure 6 PregS activates silent synapses. (A) Sample traces of whole-cell patch-clamp recording from CA1 pyramidal neurons in hippocampal slices from a P3 rat reveal mEPSCs after 25 μM PregS exposure. This effect, which is absent under control conditions, is not reversed by washout. (B) Depiction of the time course for the recordings shown in figure (A). Note that NBQX blocks this effect, indicating it is mediated by AMPA receptors. (C) Cumulative probability plot. The distribution of the mEPSC inter-event intervals at 10 vs. 25 min is not influenced by PregS exposure. Average mEPSC traces illustrating the lack of an effect of PregS on mEPSC amplitude at these time points. (D) Summary figure showing effects of vehicle (DMSO) and PregS (application represented by the gray bar) on the number of events as a function of time (n = 8–12) [From Valenzuela et al. (156) with Permission].CC BY · PubMed Central
Figure 7 Working model for the action of PregS and related neurosteroids at glutamatergic synapses in immature CA1 hippocampal pyramidal cells. (A) Under control conditions, neonatal CA1 hippocampal pyramidal neurons could have a mixture of glutamatergic synapses containing both post-synaptic AMPARs (blue) and NMDARs (red) (active synapses) or only post-synaptic NMDARs (silent synapses at rest). A “silent synapse” is enlarged. Presynaptic NMDARs are shown in orange. (B) PregS increases Ca2+ influx through presynaptic NMDARs, leading to an increase in the probability of glutamate release and activation of post-synaptic NMDARs. Pre- and post-synaptic NMDARs at these synapses are proposed to contain NR2D subunits, making them less sensitive to Mg2+ block. (C) Glutamate release probability returns to baseline levels after PregS washout. The post-synaptic increase in [Ca2+] shown in panel B elicits delayed insertion of AMPARs only in “silent synapses” [From Valenzuela et al. (156) with Permission].
Figure 7 Working model for the action of PregS and related neurosteroids at glutamatergic synapses in immature CA1 hippocampal pyramidal cells. (A) Under control conditions, neonatal CA1 hippocampal pyramidal neurons could have a mixture of glutamatergic synapses containing both post-synaptic AMPARs (blue) and NMDARs (red) (active synapses) or only post-synaptic NMDARs (silent synapses at rest). A “silent synapse” is enlarged. Presynaptic NMDARs are shown in orange. (B) PregS increases Ca2+ influx through presynaptic NMDARs, leading to an increase in the probability of glutamate release and activation of post-synaptic NMDARs. Pre- and post-synaptic NMDARs at these synapses are proposed to contain NR2D subunits, making them less sensitive to Mg2+ block. (C) Glutamate release probability returns to baseline levels after PregS washout. The post-synaptic increase in [Ca2+] shown in panel B elicits delayed insertion of AMPARs only in “silent synapses” [From Valenzuela et al. (156) with Permission].CC BY · PubMed Central
Figure 8 Picomolar concentrations of PregS increase [Ca2+]i in primary cultured cortical neurons. (A) Phase-contrast (left), fluorescence (middle), and merged (right) image of a field of cortical neurons. (B) Before (top, 0 s) and after (bottom, 19 s) application of 50 pM PregS. Regions of interest defined morphologically as neuronal cell bodies are outlined in white. (C) Mean 6 S.E.M. fluorescence intensity normalized to average initial intensity of the same cell (F/Fo) for 3 neurons in (B). (D) Baseline Ca2+ fluorescence is shown in the (left) trace. PREG (50 pM) does not increase [Ca2+]I (middle trace), whereas a subsequent application of 50 pM PregS in the presence of 50 pM PREG increases [Ca2+]i. (right trace) (mean 6 S.E.M., 30 neurons). (E) 50 pM PregS increases [Ca2+]i in primary cultured hippocampal neurons. Scale bar for (A,B): 10 mm. [From Smith et al. (48) with Permission].
Figure 8 Picomolar concentrations of PregS increase [Ca2+]i in primary cultured cortical neurons. (A) Phase-contrast (left), fluorescence (middle), and merged (right) image of a field of cortical neurons. (B) Before (top, 0 s) and after (bottom, 19 s) application of 50 pM PregS. Regions of interest defined morphologically as neuronal cell bodies are outlined in white. (C) Mean 6 S.E.M. fluorescence intensity normalized to average initial intensity of the same cell (F/Fo) for 3 neurons in (B). (D) Baseline Ca2+ fluorescence is shown in the (left) trace. PREG (50 pM) does not increase [Ca2+]I (middle trace), whereas a subsequent application of 50 pM PregS in the presence of 50 pM PREG increases [Ca2+]i. (right trace) (mean 6 S.E.M., 30 neurons). (E) 50 pM PregS increases [Ca2+]i in primary cultured hippocampal neurons. Scale bar for (A,B): 10 mm. [From Smith et al. (48) with Permission].CC BY · PubMed Central
Figure 9 Schematic illustrating pathways that may underlie pM PregS-induced [Ca2+]i and pCREB increases. Diagram illustrates 50 pM PregS-stimulated increase in [Ca2+]i via voltage-gated Na+ channels, NMDARs, and Ca2+L and 50 pM PregS-induced pCREB increases via synaptic NMDAR and ERK activation. Inhibitors used in the study are in bold. *KN93 did not inhibit PregS-induced pCREB increases. [From Smith et al. (48) with Permission].
Figure 9 Schematic illustrating pathways that may underlie pM PregS-induced [Ca2+]i and pCREB increases. Diagram illustrates 50 pM PregS-stimulated increase in [Ca2+]i via voltage-gated Na+ channels, NMDARs, and Ca2+L and 50 pM PregS-induced pCREB increases via synaptic NMDAR and ERK activation. Inhibitors used in the study are in bold. *KN93 did not inhibit PregS-induced pCREB increases. [From Smith et al. (48) with Permission].CC BY · PubMed Central
Figure 10 Schematic illustration of ABC and SLC transporters putatively involved in DHEAS and PregS transport and their proposed localization. (A) Structures of DHEAS and PregS. (B,C) The ATP-binding cassette (ABC) and solute carrier (SLC)-type membrane proteins facilitate transport of neurosteroids at the BBB and in the choroid plexus (CP) The ABC transporters BCRP (ABCG2), MRP1, MRP4, and MRP8 (ABCC1, ABCC4, and ABCC11) facilitate efflux of conjugated steroids. The solute carriers OAT3 (SLC22A3), OATP1A2 (SLCO1A2), OATP2B1 (SLCO2B1), and OSTa/ß (SLC51A/B) are implicated in secretion of sulfated steroids from neurons and glial cells and in their transport across the BBB as well as blood–CSF barrier in the CP. Arrows indicate the directions of substrate transport. Proteins for which there is little or controversial evidence for expression and localization in the basal or apical membrane are indicated in light orange and by a dashed line. The DHEAS and PregS concentration gradients across the BBB and in the CP are depicted on the right [From Grube et al. (177) with Permission].
Figure 10 Schematic illustration of ABC and SLC transporters putatively involved in DHEAS and PregS transport and their proposed localization. (A) Structures of DHEAS and PregS. (B,C) The ATP-binding cassette (ABC) and solute carrier (SLC)-type membrane proteins facilitate transport of neurosteroids at the BBB and in the choroid plexus (CP) The ABC transporters BCRP (ABCG2), MRP1, MRP4, and MRP8 (ABCC1, ABCC4, and ABCC11) facilitate efflux of conjugated steroids. The solute carriers OAT3 (SLC22A3), OATP1A2 (SLCO1A2), OATP2B1 (SLCO2B1), and OSTa/ß (SLC51A/B) are implicated in secretion of sulfated steroids from neurons and glial cells and in their transport across the BBB as well as blood–CSF barrier in the CP. Arrows indicate the directions of substrate transport. Proteins for which there is little or controversial evidence for expression and localization in the basal or apical membrane are indicated in light orange and by a dashed line. The DHEAS and PregS concentration gradients across the BBB and in the CP are depicted on the right [From Grube et al. (177) with Permission].CC BY · PubMed Central
Figure 11 Functional MRI studies show that treatment with PREG enhances activation of neural circuitry involved in emotional regulation as measured by a Shifted-Attention Emotion Appraisal (SEAT) paradigm. The SEAT task is designed to probe multiple aspects of emotional regulation in response to presentation of images depicting neutral, angry, or fearful expressions superimposed on pictures of indoor or outdoor scenes. Sixteen subjects were treated with PREG and 15 were treated with placebo (PBO). Subjects viewed the stimuli through MR-compatible goggles and responded using an MRI-compatible button box. Maps of cerebral activation in each condition indicated that: (A) There was a significant (p < 0.05) main effect of drug in the amygdala [Montreal Institute (MNI) coronal (y) plane coordinate = 2] and right insula [MNI axial (z) plane coordinate = −6] such that, treatment with PREG decreased activity in these two regions across all conditions and face types. (B) Treatment with PREG increased activation in dorsal medial prefrontal cortex (dmPFC) [MNI sagittal (x) plane coordinate = 0] during appraisal. (C) PREG treatment also significantly (p < 0.001) increased functional connectivity between the dmPFC and left amygdala during appraisal. Self-reported anxiety was inversely correlated (r = −0.52, p = 0.046) with functional connectivity between the dmPFC and amygdala in the PREG group. Percent signal change is displayed next to each figure [Modified from Sripada et al. (192) with Permission].
Figure 11 Functional MRI studies show that treatment with PREG enhances activation of neural circuitry involved in emotional regulation as measured by a Shifted-Attention Emotion Appraisal (SEAT) paradigm. The SEAT task is designed to probe multiple aspects of emotional regulation in response to presentation of images depicting neutral, angry, or fearful expressions superimposed on pictures of indoor or outdoor scenes. Sixteen subjects were treated with PREG and 15 were treated with placebo (PBO). Subjects viewed the stimuli through MR-compatible goggles and responded using an MRI-compatible button box. Maps of cerebral activation in each condition indicated that: (A) There was a significant (p < 0.05) main effect of drug in the amygdala [Montreal Institute (MNI) coronal (y) plane coordinate = 2] and right insula [MNI axial (z) plane coordinate = −6] such that, treatment with PREG decreased activity in these two regions across all conditions and face types. (B) Treatment with PREG increased activation in dorsal medial prefrontal cortex (dmPFC) [MNI sagittal (x) plane coordinate = 0] during appraisal. (C) PREG treatment also significantly (p < 0.001) increased functional connectivity between the dmPFC and left amygdala during appraisal. Self-reported anxiety was inversely correlated (r = −0.52, p = 0.046) with functional connectivity between the dmPFC and amygdala in the PREG group. Percent signal change is displayed next to each figure [Modified from Sripada et al. (192) with Permission].CC BY · PubMed Central
Figure 12 Event-related fMRI studies in female subjects showing effects of progesterone on brain regions involved in the encoding and retrieval of memories of faces. Results of conjunction analyses for the relationships between neural activity in different brain regions and memory performance across subjects. (A) During encoding of memories for faces, progesterone administration was associated with reduced activity in the right amygdala (MNI coronal (y) plane coordinate = −12; p < 0.001, uncorrected) and fusiform gyrus [MNI coronal (y) plane coordinate = −52] which predicted a decrease in memory performance across subjects. (B) Parameter estimates for mean activity within each significant conjunction cluster (SH = subsequent hits; SM = subsequent misses; a.u. = arbitrary units; mean ± SEM). (C) The progesterone-induced decrease in amygdalar activity predicted the decrease in memory performance across subjects [recognition memory accuracy = d′]. (D–F) Identical figures for the significant conjunction of main effects in the right fusiform gyrus and memory performance. Progesterone reduces activity in the fusiform and inferior frontal gyri and impairs performance during retrieval of memories for faces. (G) Significant conjunction of main effect of memory (i.e., hits > misses) and main effect of drug [i.e., placebo (faces > null events) > progesterone (faces > null events)] in the right fusiform gyrus [MNI coronal (y) plane coordinate = −56; p < 0.001, uncorrected]. (H) Parameter estimates of the conjunction cluster (arbitrary units; mean ± SEM). (I) Progesterone-induced reduction in fusiform gyrus activity predicted the decrease in memory performance across subjects [recognition memory accuracy (d′)]. (J–L) Identical figures for the significant conjunction of main effects in the left inferior frontal gyrus [MNI coronal (y) plane coordinate = 26]. H, Hits; M, misses; a.u., arbitrary units. H, Hits; M, misses; a.u., arbitrary units [Modified from van Wingen et al. (64) with Permission].
Figure 12 Event-related fMRI studies in female subjects showing effects of progesterone on brain regions involved in the encoding and retrieval of memories of faces. Results of conjunction analyses for the relationships between neural activity in different brain regions and memory performance across subjects. (A) During encoding of memories for faces, progesterone administration was associated with reduced activity in the right amygdala (MNI coronal (y) plane coordinate = −12; p < 0.001, uncorrected) and fusiform gyrus [MNI coronal (y) plane coordinate = −52] which predicted a decrease in memory performance across subjects. (B) Parameter estimates for mean activity within each significant conjunction cluster (SH = subsequent hits; SM = subsequent misses; a.u. = arbitrary units; mean ± SEM). (C) The progesterone-induced decrease in amygdalar activity predicted the decrease in memory performance across subjects [recognition memory accuracy = d′]. (D–F) Identical figures for the significant conjunction of main effects in the right fusiform gyrus and memory performance. Progesterone reduces activity in the fusiform and inferior frontal gyri and impairs performance during retrieval of memories for faces. (G) Significant conjunction of main effect of memory (i.e., hits > misses) and main effect of drug [i.e., placebo (faces > null events) > progesterone (faces > null events)] in the right fusiform gyrus [MNI coronal (y) plane coordinate = −56; p < 0.001, uncorrected]. (H) Parameter estimates of the conjunction cluster (arbitrary units; mean ± SEM). (I) Progesterone-induced reduction in fusiform gyrus activity predicted the decrease in memory performance across subjects [recognition memory accuracy (d′)]. (J–L) Identical figures for the significant conjunction of main effects in the left inferior frontal gyrus [MNI coronal (y) plane coordinate = 26]. H, Hits; M, misses; a.u., arbitrary units. H, Hits; M, misses; a.u., arbitrary units [Modified from van Wingen et al. (64) with Permission].CC BY · PubMed Central
Figure 13 Pregnanolone hemisuccinate (3α5βHS) is neuroprotective in an in vivo model of stroke. Rats were infused with either vehicle or 3α5βHS (6.9 mg/kg/h; 6.9 mg/kg loading dose), beginning immediately or 30 min after initiation of medial cerebral artery occlusion. Infusion of 3α5βHS was continued for an additional 22 h, at which time the rats were euthanized and their brains harvested and stained with 2,3,5-triphenyl tetrazolium Cl. (A) Representative coronal sections from animals receiving vehicle or 3α5βHS infusions immediately after initiation of ischemia. Infarct area appears pale. (B) Administration of 3α5βHS immediately after the onset of ischemia significantly reduced the volume of the cortical infarct from 206 ± 22 to 110 ± 21 mm3 (P < 0.005) and subcortical infarct was reduced from 103 ± 6 to 76 ± 6 mm3 (*P < 0.005) (vehicle, n = 9; 3α5βHS, n = 10). (C) When 3α5βHS was administered 30 min after the onset of ischemia the volume of cortical infarct was reduced from 173 ± 15 to 106 ± 15 mm3 (*P < 0.005; n = 13), with no reduction apparent in the subcortical region [From Weaver et al. (132) with Permission].
Figure 13 Pregnanolone hemisuccinate (3α5βHS) is neuroprotective in an in vivo model of stroke. Rats were infused with either vehicle or 3α5βHS (6.9 mg/kg/h; 6.9 mg/kg loading dose), beginning immediately or 30 min after initiation of medial cerebral artery occlusion. Infusion of 3α5βHS was continued for an additional 22 h, at which time the rats were euthanized and their brains harvested and stained with 2,3,5-triphenyl tetrazolium Cl. (A) Representative coronal sections from animals receiving vehicle or 3α5βHS infusions immediately after initiation of ischemia. Infarct area appears pale. (B) Administration of 3α5βHS immediately after the onset of ischemia significantly reduced the volume of the cortical infarct from 206 ± 22 to 110 ± 21 mm3 (P < 0.005) and subcortical infarct was reduced from 103 ± 6 to 76 ± 6 mm3 (*P < 0.005) (vehicle, n = 9; 3α5βHS, n = 10). (C) When 3α5βHS was administered 30 min after the onset of ischemia the volume of cortical infarct was reduced from 173 ± 15 to 106 ± 15 mm3 (*P < 0.005; n = 13), with no reduction apparent in the subcortical region [From Weaver et al. (132) with Permission].CC BY · PubMed Central
Figure 14 Pharmacologic connectivity pathways implicated in neurosteroidal modulation of memory function. Neural networks that project to and/or share reciprocal connections with the hippocampus are modulated by neurosteroids as well as neurotransmitters. As a result, learning and memory deficits are associated with many of neurologic and neuropsychiatric disorders in which neurosteroids are implicated. The amygdala (shown in red), which is implicated in anxiety disorders, shares reciprocal connections with the hippocampus (shown in green). Progesterone, which is metabolized to ALLO, modulates emotional memory function by influencing amygdalar activity (64). The effects of neurosteroids on learning and memory for fear-inducing stimuli appears to be different in males and females which show different brain levels of ALLO at baseline as well (395). Neuroactive steroids, such as ALLO that enhance inhibitory neurotransmission can provide symptomatic relief from anxiety by reducing intra-network connectivity in the salience network and the amygdala (75, 192, 290, 291). ALLO induces an increase in functional connectivity between the amygdala and prefrontal cortex (shown in blue), which is involved in processing of complex social and non-social stimuli. However, the increased inhibition associated higher levels of ALLO can also interfere with episodic memory function which depends on intact functional connectivity between the hippocampus and the pre-cuneus (not shown) (203). Interestingly, both PREG, which is metabolized to ALLO, and PregS, which is a positive modulator of NMDARs, improve working memory function in patients with schizophrenia in which cortical disinhibition due to hypofunction of excitatory NMDARs on PV interneurons in the prefrontal cortex has been implicated (51, 52, 65, 237, 238). Parahippocampal and hippocampal structures including, the trisynaptic circuit receives sensory and emotional inputs from sensory modalities via the thalamus (shown in orange) and the amygdala, respectively (396–398). The impact of powerful emotion-evoking stimuli are state independent when ALLO is injected into the amygdala and hippocampus, but state-dependent when it is injected into the BNST (shown in gray) (246). The response of the hippocampal trisynaptic circuit to neurosteroids also depends on disease state-dependent changes in neurosteroid biosynthesis and receptor expression (399–401), as well as age-related changes in steroid hormone levels which converge to influence the responsivity of this circuit to endogenous and exogenous sources of neurosteroids and their synthetic analogs (229, 401–403).
Figure 14 Pharmacologic connectivity pathways implicated in neurosteroidal modulation of memory function. Neural networks that project to and/or share reciprocal connections with the hippocampus are modulated by neurosteroids as well as neurotransmitters. As a result, learning and memory deficits are associated with many of neurologic and neuropsychiatric disorders in which neurosteroids are implicated. The amygdala (shown in red), which is implicated in anxiety disorders, shares reciprocal connections with the hippocampus (shown in green). Progesterone, which is metabolized to ALLO, modulates emotional memory function by influencing amygdalar activity (64). The effects of neurosteroids on learning and memory for fear-inducing stimuli appears to be different in males and females which show different brain levels of ALLO at baseline as well (395). Neuroactive steroids, such as ALLO that enhance inhibitory neurotransmission can provide symptomatic relief from anxiety by reducing intra-network connectivity in the salience network and the amygdala (75, 192, 290, 291). ALLO induces an increase in functional connectivity between the amygdala and prefrontal cortex (shown in blue), which is involved in processing of complex social and non-social stimuli. However, the increased inhibition associated higher levels of ALLO can also interfere with episodic memory function which depends on intact functional connectivity between the hippocampus and the pre-cuneus (not shown) (203). Interestingly, both PREG, which is metabolized to ALLO, and PregS, which is a positive modulator of NMDARs, improve working memory function in patients with schizophrenia in which cortical disinhibition due to hypofunction of excitatory NMDARs on PV interneurons in the prefrontal cortex has been implicated (51, 52, 65, 237, 238). Parahippocampal and hippocampal structures including, the trisynaptic circuit receives sensory and emotional inputs from sensory modalities via the thalamus (shown in orange) and the amygdala, respectively (396–398). The impact of powerful emotion-evoking stimuli are state independent when ALLO is injected into the amygdala and hippocampus, but state-dependent when it is injected into the BNST (shown in gray) (246). The response of the hippocampal trisynaptic circuit to neurosteroids also depends on disease state-dependent changes in neurosteroid biosynthesis and receptor expression (399–401), as well as age-related changes in steroid hormone levels which converge to influence the responsivity of this circuit to endogenous and exogenous sources of neurosteroids and their synthetic analogs (229, 401–403).CC BY · PubMed Central

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  1. Weaver, 2000, Geometry and charge determine the pharmacological effects of steroids on the N-methyl-D-aspartate receptor, J Pharmacol Exp Ther, 293, 747

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Authors
Ratner, M. H., Kumaresan, V., & Farb, D. H.
Affiliations
Boston University (US)
Corresponding author
Farb, David H.
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2019-04-09
Volume
10
Pages
169-169
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2019.00169
PMC
PMC6465949
OpenAlex
W2939309394
Cited by
96
References
412
Citations by year
2026: 5 · 2025: 4 · 2024: 14 · 2023: 16 · 2022: 18 · 2021: 22 · 2020: 15 · 2019: 1
FWCI
1.86
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging (R21AG056947)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
neurosteroids, memory, GABAA receptor, NMDA receptor, non-NMDA receptors, allosteric modulation, neuromodulation, neural circuits, memory impairment, neuropsychiatric disorders, neurodegenerative diseases, sex differences

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