Molecular Psychiatry (2015) 20, 18–22 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp EXPERT REVIEW Estrogen receptor β and Liver X receptor β: biology and therapeutic potential in CNS diseases M Warner1 and J-A Gustafsson1,2 In the last decade of the twentieth century, two nuclear receptors were discovered in our laboratory and, very surprisingly, were found to have key roles in the central nervous system. These receptors have provided some novel insights into the etiology and progression of neurodegenerative diseases and anxiety disorders. The two receptors are estrogen receptor beta (ERβ) and liver X receptor beta (LXRβ). Both ERβ and LXRβ have potent anti-inflammatory activities and, in addition, LXRβ is involved in the genesis of dopaminergic neurons during development and protection of these neurons against neurodegeneration in adult life. ERβ is involved in migration of cortical neurons and calretinin-positive GABAergic interneurons during development and maintenance of serotonergic neurons in adults. Both receptors are present in magnocellular neurons of the hypothalamic preoptic area including those expressing vasopressin and oxytocin. As both ERβ and LXRβ are ligand-activated transcription factors, their ligands hold great potential in the treatment of diseases of the CNS. Molecular Psychiatry (2015) 20, 18–22; doi:10.1038/mp.2014.23; published online 25 March 2014 HISTORICAL PERSPECTIVE: ERβ simultaneously discovered in other laboratories and found to be a Estrogen receptor beta (ERβ) was discovered in 1995 and reported close relative of another orphan receptor, Liver X receptor (LXR) α 23 in 1996.1–12 It is the second estrogen receptor in the body, discovered in transcripts from the liver. Because of the transcribed from a gene on chromosomen14,13 different from the homology between the two orphan receptors, OR-1 was renamed well-known estrogen receptor now called ERα, which resides on LXRβ. The name is slightly misleading because LXRβ is not highly chromosome 6.14 At estrogen response elements on DNA, ERβ is a expressed in the liver but is expressed in the immune system, weaker transactivator than is ERα and when the two receptors are brain and epithelium of the lining of the gut. Loss of LXRβ results 24 co-expressed in cells, ERβ may dampen the activity of ERα.15 in pancreatitis and gallbladder inflammation leading eventually 25 However, there are many places in the body where ERβ is to gallbladder cancer. The endogenous ligands for both LXRs are 26 exclusively expressed and in these cells it is ERβ that mediates the thought to be oxysterols. transcriptional activity of estrogen. In the developing brain, ERβ is detectable at E12.5 when ERα is not and is very abundant in the outer layers of the cerebral cortex but not in the ventricular or LXR IN NEURODEGENERATIVE DISEASES β subventricular zones (Figure 1). ER is expressed in microglia and β oligodendrocytes16 and neurons of the dorsal raphe,8 the hypotha- Knockout of LXR in male (but not female) mice, leads to 17 symptoms of both motor neuron disease and Parkinson’s disease lamic preoptic area (Figure 2) and hippocampus. ERα is expressed 27–29 in astrocytes,18 neurons of the periductal gray,19 in certain neurons (PD). The CNS of these mice is characterized by loss of motor of the hypothalamic preoptic area, hippocampus (different from neurons in the lateroventral horns of L1 segments of the spinal those expressing ERβ) and in spinal motor neurons.20 cord, loss of dopaminergic neurons in the substantia nigra There are two interesting aspects of ERβ signaling which make (Figure 3) and accumulation of activated microglia and astrogliosis it novel as a pharmacological target. The first is that gene in the damaged areas. Co-occurrence of PD and motor neuron regulation by ERβ at AP1 and SP1 sites is opposite to that of ERα.21 disease is rare except in amyotrophic lateral sclerosis (ALS) parkinsonism-dementia complex which occurs in the native At these response elements, ERβ in the absence of ligand is a 30 repressor and in the presence of tamoxifen it is a transcriptional people of Guam. activator. E2 does not influence activity of ERβ at AP1 sites. The LXRs are ligand-activated regulators of the transcription of second interesting aspect is that ERβ is not expressed in the genes involved in cholesterol homeostasis. Genes of key importance are the reverse cholesterol transporters, which remove pituitary or in the uterine epithelium and ERβ-selective ligands do 31 not cause chemical castration nor do they elicit uterine growth. cholesterol from cells and those involved in bile acid synthesis and cholesterol elimination.32 Although ALS patients have not been examined for abnormalities in LXRs, there is a report that in male but not female ALS patients, serum levels of cholesterol and HISTORICAL PERSPECTIVE: LXRβ triglycerides were significantly lower than in male controls.33 LXR Liver X receptor beta (LXRβ) was the first orphan receptor agonists do increase levels of triglycerides and such lower levels discovered in our laboratory and we called it OR-1.22 It was are compatible with loss of LXR. 1Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA and 2Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Stockholm, Sweden. Correspondence: Professor J-A Gustafsson, Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, 3605 Cullen Boulevard, Science & Engineering Research Center Building 545, Houston, TX 77204, USA. E-mail: [email protected] Received 24 January 2014; accepted 3 February 2014; published online 25 March 2014 Role of ERβ and LXRβ in CNS diseases M Warner and J-A Gustafsson 19 Figure 1. ERα and ERβ immunostaining in the mouse brain at E18.5. The antibodies used were: a homemade ERβ antibody raised in chickens against the N-terminally deleted ERβ protein; commercial ERα antibody MC20 from Santa Cruz, CA, USA. Figure 2. ERβ staining in the HPOA of the mouse brain at P14. (b, c) Shows high enlargement of the regions indicated in a. treatment. It is a rapidly progressing fatal disease which occurs predominantly in adult males. The reason for the gender differ- ence is unknown. Spinal cord motor neurons express ERα where it has a role in protecting neurons against toxicity of cytokines.35 Because of the differences in estrogen levels between males and females, male motor neurons may be less well protected from the destructive effects of cytokines than those of females. Neuroinflammation has a major role in the progression of PD.36 Under most conditions, glucocorticoids are the frontline treatment for inflammation.37 Unfortunately, synthetic glucocorticoids have low brain penetrability, are actively removed from the brain and, upon long-term treatment, are associated with devastating bone loss. Pharmaceutical companies have produced ERβ agonists some of which are powerful anti-inflammatory agents and some are being investigated as alternatives to glucocorticoids to combat 38–43 Figure 3. At 2 weeks of age there are fewer neurons in the neuroinflammation. substantia nigra of LXRβ − / − than in WT mice. WT, wild type. ERβ SELECTIVE LIGANDS IN NEURODEGENERATIVE DISEASES Several groups have investigated the role of synthetic ERβ- As with PD, the etiology of parkinsonism-dementia complex is selective agonists in mouse models of neuroinflammation. Spence unknown. PD is a progressive neurological disease, which affects et al.18 have found that both ERα and ERβ offer protection in 1% of the population over 55 years of age. Although genetic experimental autoimmune encephalitis mouse. The effect of mutations have been identified in familial PD, the etiology of ERα is through astrocytes but the cells involved in ERβ-mediated spontaneous PD, which accounts for more than 90% of cases, protection were not identified. Although there are some reports of remains unknown.34 Until a specific gene defect is identified, expression of ERα in microglia44,45 we have found that ERβ, not targeted therapy is not possible. At present, therapy is focused on ERα, is expressed in human and rodent microglia.43 Microglia are treatment of symptoms. For motor neuron disease, there is no the macrophages in the brain and when they are activated can © 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 18 – 22 Role of ERβ and LXRβ in CNS diseases M Warner and J-A Gustafsson 20 damage healthy neurons in the vicinity of damage or infection.46 and contribute to the etiology of depression and substance ERβ-selective ligands can dampen activation of microglia, reduce abuse.54–57 The ventromedial PFC, amygdala and dorsal raphe, the proinflammatory potential of invading T cells, and stimulate are key brain areas involved in emotional processing. Inhibitory oligodendrocytes43 improving survival and promoting recovery in GABAergic outputs from the ventromedial PFC suppress the experimental autoimmune encephalitis mice. amygdala to modulate fear and anxiety. When this input is disrupted, loss of inhibition of the amygdala leads to exaggerated amygdala activation which results in anxiety and depressed mood LXRβ IN THE MPTP MOUSE MODEL OF PARKINSON’S DISEASE disorders.57,58 Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine One of the important genes regulated by LXRβ in the PFC, is (MPTP) to mice leads to destruction of dopaminergic neurons in GAD (glutamic acid decarboxylase), the enzyme which catalyzes the substantia nigra, and administration of MPTP is used as a the synthesis of GABA from glutamic acid. In LXRβ − / − mice, the model of chemical induction of Parkinson’s symptoms. In wild- number of GAD-positive interneurons in the ventromedial PFC, is type mice, administration of the LXRβ agonist, GW3965, to MPTP- reduced whereas in other areas of the cortex, hippocampus and treated wild-type mice protects against loss of dopaminergic Purkinje cells in cerebellum, expression of GAD is normal.53 neurons and of dopaminergic fibers projecting to the striatum and Expression of tryptophan hydroxylase 2 (TPH2) in the dorsal raphe, resulted in fewer activated microglia and astroglia.47 When MPTP which controls excitability in the PFC,53 was also normal.