Hippocampal nitric oxide contributes to sex difference in affective behaviors

Abstract

Mechanisms underlying the female preponderance in affective disorders are poorly understood. Here we show that hippocampal nitric oxide (NO) plays a role in the sex difference of depressionlike behaviors in rodents. Female mice had substantially lower NO production in the hippocampus and were significantly more likely to display negative affective behaviors than their male littermates. Eliminating the difference in the basal hippocampal NO level between male and female mice mended the sex gap of affective behaviors. Estradiol exerted a positive control on hippocampal NO production via estrogen receptor-β-mediated neuronal NO synthase expression. Thus, low estrogen in the female hippocampus accounts for lower local NO than in the male hippocampus. Although estrogen has important significance in modulating affective behaviors, it is not estrogen but NO in the hippocampus that mediates the sex difference of affective behaviors directly, because hippocampal NO was necessary for the behavioral effects of estradiol, and NO was an independent factor in modulating behaviors. Stress promoted hippocampal NO production in males because of glucocorticoid release, thus leading to local NO excess. In contrast, stress suppressed NO production in females because of decreased estrogen, thereby resulting in hippocampal NO shortage. Whereas activating cAMP response element binding protein (CREB) rescued the depression-like effects of the intrahippocampal NO donor diethylenetriamine/nitric oxide adduct (DETA/NONOate), inactivating CREB abolished the antidepressant-like effects of the intrahippocampal NO donor DETA/NONOate. Our findings suggest a molecular mechanism underlying the sex difference of affective behaviors.A ffective disorders such as depression and anxiety, lifethreatening and highly prevalent stress-related disorders, rank among the top causes of worldwide disease burden and disability (1, 2). It is commonly suggested that a female preponderance in depression and anxiety is universal and substantial. The prevalence of depression and anxiety for women is approximately twice that for men (2-6). Although there are advocates for the implications of hypothalamic-pituitary-adrenal axis hyperactivity in the sex differentiation in some expressions of both depression and anxiety (7), it is not clear what underlies the sex gap in these affective disorders.Neuronal nitric oxide synthase (nNOS) has been implicated in the psychiatric disorders characterized by depression (8, 9), schizophrenia (10), and aggressiveness (11). We recently demonstrated that hippocampal nNOS mediates the stress-related depressive behaviors of glucocorticoids (9) and the role of 5-hydroxytryptamine receptor 1A (5-HT1A) receptor in modulating anxiety-related behaviors (12). Evidence from clinical and biological studies indicates that the hippocampus plays an important role in major depression disorder (13). We found that chronic mild stress (CMS) increased hippocampal NO production by nNOS in male mice (6-9). In contrast, CMS diminished hippocampal NO prod...

Do cortical plasticity mechanisms differ between males and females?

“…The dependence of male plasticity on NO may relate to baseline differences between the sexes. Females have, within the hippocampus, less abundant NO and reduced NOS1 expression compared with males, although the application of estradiol increases hippocampal NOS1 expression (Hu et al, ). Therefore, a possible explanation for this sex difference is that females lack available NO for the induction of plasticity and thus rely on other molecular pathways instead.…”

“…Recent studies have also demonstrated a role for E2 in inhibition and hve begun to reveal not only that is this sex specific but that E2 acts through distinct molecular pathways. Acute E2 application to hippocampal slices has revealed a rapid suppression of GABAergic inhibitory synaptic transmission at perisomatic inputs to pyramidal cells within the hippocampal CA1, specifically through a molecular cascade including the α form of the estrogen receptor (ERα), metabotrophic glutamate receptor 1 (mGluR1), and endocannabinoid receptor 1 (Huang and Woolley ). Remarkably, this inhibitory effect was evident only in females; E2 had no effect on inhibitory postsynaptic currents (IPSCs) in males (Huang and Woolley ).…”

“…Acute E2 application to hippocampal slices has revealed a rapid suppression of GABAergic inhibitory synaptic transmission at perisomatic inputs to pyramidal cells within the hippocampal CA1, specifically through a molecular cascade including the α form of the estrogen receptor (ERα), metabotrophic glutamate receptor 1 (mGluR1), and endocannabinoid receptor 1 (Huang and Woolley ). Remarkably, this inhibitory effect was evident only in females; E2 had no effect on inhibitory postsynaptic currents (IPSCs) in males (Huang and Woolley ). Further work revealed this was because E2 promotes an ERα–mGluR1 interaction only in females, which in turn stimulates production of phospholipase C and inositol triphosphate (IP 3 ), leading to postsynaptic endocannabinoid release (Tabatadze, 2015).…”

Estrogen Signaling and the Aging Brain: Context-Dependent Considerations for Postmenopausal Hormone Therapy

“…Moreover, decreased ER β mRNA in postmortem locus coeruleus has been found to correlate with suicide [13], and, even more recently, ER β -mediated hippocampal nitric oxide levels have been implicated in affective behaviors in females, but not males [171]. Neurotransmitter release from these regions influences mood, affect, and stress responses, and E 2 increases the rate of monoamine oxidase degradation and serotonin transport which enhances serotonin at the synapse; E 2 also increases serotonin receptor expression [172, 173].…”

Behavioral Effects of Inhibition of Cyclic Nucleotide Phosphodiesterase 2 (PDE2) in Mice

“…Previous research has shown that following repeated stress, either restraint stress or unpredictable stress, results in increases in NOS-NO levels in numerous brain regions, including the cortex and hippocampus (Gao et al, 2014;Harooni et al, 2009;Hu et al, 2012;Zhou et al, 2011). It is likely these increases in NO lead to increases in cGMP levels as well (Meyerhoff et al, 1985;Southam and Garthwaite, 1993).…”