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Sex Differences in Molecular Signaling at Inhibitory Synapses in the Hippocampus.
J Neurosci. 2015 Aug 12; 35(32):11252-65.JN

Abstract

The possibility that mechanisms of synaptic modulation differ between males and females has far-reaching implications for understanding brain disorders that vary between the sexes. We found recently that 17β-estradiol (E2) acutely suppresses GABAergic inhibition in the hippocampus of female rats through a sex-specific estrogen receptor α (ERα), mGluR, and endocannabinoid-dependent mechanism. Here, we define the intracellular signaling that links ERα, mGluRs, and endocannabinoids in females and identify where in this pathway males and females differ. Using a combination of whole-cell patch-clamp recording and biochemical analyses in hippocampal slices from young adult rats, we show that E2 acutely suppresses inhibition in females through mGluR1 stimulation of phospholipase C, leading to inositol triphosphate (IP3) generation, activation of the IP3 receptor (IP3R), and postsynaptic endocannabinoid release, likely of anandamide. Analysis of sex differences in this pathway showed that E2 stimulates a much greater increase in IP3 levels in females than males, whereas the group I mGluR agonist DHPG increases IP3 levels equivalently in each sex. Coimmunoprecipitation showed that ERα-mGluR1 and mGluR1-IP3R complexes exist in both sexes but are regulated by E2 only in females. Independently of E2, a fatty acid amide hydrolase inhibitor, which blocks breakdown of anandamide, suppressed >50% of inhibitory synapses in females with no effect in males, indicating tonic endocannabinoid release in females that is absent in males. Together, these studies demonstrate sex differences in both E2-dependent and E2-independent regulation of the endocannabinoid system and suggest that manipulation of endocannabinoids in vivo could affect physiological and behavioral responses differently in each sex.

SIGNIFICANCE STATEMENT

Many brain disorders vary between the sexes, yet the degree to which this variation arises from differential experience versus intrinsic biological sex differences is unclear. In this study, we demonstrate intrinsic sex differences in molecular regulation of a key neuromodulatory system, the endocannabinoid system, in the hippocampus. Endocannabinoids are involved in diverse aspects of physiology and behavior that involve the hippocampus, including cognitive and motivational state, responses to stress, and neurological disorders such as epilepsy. Our finding that molecular regulation of the endocannabinoid system differs between the sexes suggests mechanisms through which experiences or therapeutics that engage endocannabinoids could affect males and females differently.

Authors+Show Affiliations

Department of Neurobiology, Northwestern University, Evanston, Illinois 60208.Department of Neurobiology, Northwestern University, Evanston, Illinois 60208.Department of Neurobiology, Northwestern University, Evanston, Illinois 60208.Department of Neurobiology, Northwestern University, Evanston, Illinois 60208.Department of Neurobiology, Northwestern University, Evanston, Illinois 60208 cwoolley@northwestern.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26269634

Citation

Tabatadze, Nino, et al. "Sex Differences in Molecular Signaling at Inhibitory Synapses in the Hippocampus." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 35, no. 32, 2015, pp. 11252-65.
Tabatadze N, Huang G, May RM, et al. Sex Differences in Molecular Signaling at Inhibitory Synapses in the Hippocampus. J Neurosci. 2015;35(32):11252-65.
Tabatadze, N., Huang, G., May, R. M., Jain, A., & Woolley, C. S. (2015). Sex Differences in Molecular Signaling at Inhibitory Synapses in the Hippocampus. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 35(32), 11252-65. https://doi.org/10.1523/JNEUROSCI.1067-15.2015
Tabatadze N, et al. Sex Differences in Molecular Signaling at Inhibitory Synapses in the Hippocampus. J Neurosci. 2015 Aug 12;35(32):11252-65. PubMed PMID: 26269634.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sex Differences in Molecular Signaling at Inhibitory Synapses in the Hippocampus. AU - Tabatadze,Nino, AU - Huang,Guangzhe, AU - May,Renee M, AU - Jain,Anant, AU - Woolley,Catherine S, PY - 2015/8/14/entrez PY - 2015/8/14/pubmed PY - 2015/11/6/medline KW - GABA KW - endocannabinoid KW - estradiol KW - metabotropic glutamate receptor SP - 11252 EP - 65 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 35 IS - 32 N2 - UNLABELLED: The possibility that mechanisms of synaptic modulation differ between males and females has far-reaching implications for understanding brain disorders that vary between the sexes. We found recently that 17β-estradiol (E2) acutely suppresses GABAergic inhibition in the hippocampus of female rats through a sex-specific estrogen receptor α (ERα), mGluR, and endocannabinoid-dependent mechanism. Here, we define the intracellular signaling that links ERα, mGluRs, and endocannabinoids in females and identify where in this pathway males and females differ. Using a combination of whole-cell patch-clamp recording and biochemical analyses in hippocampal slices from young adult rats, we show that E2 acutely suppresses inhibition in females through mGluR1 stimulation of phospholipase C, leading to inositol triphosphate (IP3) generation, activation of the IP3 receptor (IP3R), and postsynaptic endocannabinoid release, likely of anandamide. Analysis of sex differences in this pathway showed that E2 stimulates a much greater increase in IP3 levels in females than males, whereas the group I mGluR agonist DHPG increases IP3 levels equivalently in each sex. Coimmunoprecipitation showed that ERα-mGluR1 and mGluR1-IP3R complexes exist in both sexes but are regulated by E2 only in females. Independently of E2, a fatty acid amide hydrolase inhibitor, which blocks breakdown of anandamide, suppressed >50% of inhibitory synapses in females with no effect in males, indicating tonic endocannabinoid release in females that is absent in males. Together, these studies demonstrate sex differences in both E2-dependent and E2-independent regulation of the endocannabinoid system and suggest that manipulation of endocannabinoids in vivo could affect physiological and behavioral responses differently in each sex. SIGNIFICANCE STATEMENT: Many brain disorders vary between the sexes, yet the degree to which this variation arises from differential experience versus intrinsic biological sex differences is unclear. In this study, we demonstrate intrinsic sex differences in molecular regulation of a key neuromodulatory system, the endocannabinoid system, in the hippocampus. Endocannabinoids are involved in diverse aspects of physiology and behavior that involve the hippocampus, including cognitive and motivational state, responses to stress, and neurological disorders such as epilepsy. Our finding that molecular regulation of the endocannabinoid system differs between the sexes suggests mechanisms through which experiences or therapeutics that engage endocannabinoids could affect males and females differently. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/26269634/Sex_Differences_in_Molecular_Signaling_at_Inhibitory_Synapses_in_the_Hippocampus_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=26269634 DB - PRIME DP - Unbound Medicine ER -