Review
Role of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas

https://doi.org/10.1016/j.yhbeh.2007.12.007Get rights and content

Abstract

Accumulating evidence indicate that structural synaptic plasticity in limbic areas plays a vital role not only in normal brain functions, such as cognition and mood, but also in the development of neurological and mental disorders. We have learned from studies investigating neuronal remodeling that estrogens have an exceptional synaptogenic potential that seems to be specific to limbic areas of the adult female brain. On the other hand, structural synaptic plasticity in the adult male brain and the synaptogenic effect of androgens received relatively little attention. During the last five years, the Leranth laboratory provided conclusive evidence that the hippocampus and prefrontal cortex of adult male rodents and non-human primates retain considerable structural synaptic plasticity similar to the female, and that androgens are capable of inducing spine synapse growth in both the hippocampus and prefrontal cortex similar to estrogens. Our recent work also demonstrates that androgen-induced remodeling of spine synapses in the prefrontal cortex of adult male rats is dependent, at least to some extent, on functional androgen receptors, while being entirely independent of the androgen receptor in the hippocampus. Based on these findings and on their many beneficial effects, we believe that androgens hold a great and undeservingly neglected therapeutic potential that could be employed to reverse synaptic pathology in various neurocognitive and neuropsychiatric disorders.

Introduction

During recent years, the conventional view of the adult brain as an anatomically “fixed” structure has dramatically changed. As the pace of new developments has accelerated, there is now widespread acceptance of the idea that even the adult mammalian brain retains considerable structural plasticity. Neurogenesis continues in adulthood, while synapses are dynamically lost and formed, sometimes with extraordinary rapidity. More importantly, accumulating evidence indicate that structural synaptic plasticity in limbic areas plays a vital role not only in normal brain functions, such as cognition and mood, but also in the development of neurological and mental disorders. All of these have evolved from a most unexpected source. The initial observations and much of the ensuing evidence have come from studies on the effects of steroid hormones, the sex steroids playing a particularly important role. Much of the work on sex steroid-induced neuroplasticity has focused on the effects of estrogens, which participate in orchestrating sexual differentiation in development, as well as modulating adult hypothalamic and limbic structures (Parducz et al., 2006). Since 2003, when we have reported that hippocampal spine synapse growth in castrated, adult male rats cannot be induced by estradiol but it is triggered by androgens (Leranth et al., 2003), it has become clear that androgens are capable of modulating structural synaptic plasticity in the adult brain via mechanisms considerably different from those utilized by estrogens. As a result, more studies and exciting findings have followed, both from our and other laboratories, most of which are summarized in this review.

Section snippets

Androgens and higher brain functions

It is less known, surprisingly, that in both men and women, androgens comprise a substantial component of the total circulating pool of sex steroids in young adults, but then their production declines markedly with age. Circulating levels of the adrenal androgen, dehydroepiandrosterone (DHEA), in particular, undergo a precipitous drop over the course of middle age, falling more than 70% between the 3rd and 6th decades of life (Labrie et al., 2003). It has been hypothesized that such a change in

Androgen-induced spine synapse formation in the hippocampus

Why is structural synaptic plasticity in limbic brain areas so important to study? Because based on mounting evidence, it appears that growth of dendritic spines and formation of their synapses represent a morphological substrate for learning and memory (Geinisman et al., 2001, Kasai et al., 2003, Lang et al., 2004, Silva, 2003). Moreover, in a recent review article, we have proposed that remodeling of hippocampal spine synapses may play a critical role in the mechanisms of depression and

Androgen-induced spine synapse formation in the prefrontal cortex

While much of the work on the synaptogenic effects of sex steroids so far has focused on the CA1 area, it is important to recognize that this phenomenon is clearly not confined to the hippocampus. In humans, non-human primates, and rats, the prefrontal cortex is also involved in cognitive, emotional, and locomotor functions, including spatial orientation, habituation, temporal ordering, and most importantly, working memory (Kolb, 1984). Similar to the hippocampus, there is growing evidence that

Is the androgen receptor involved — or not?

We have concluded above that in certain cases, androgens induce the formation of CA1 spine synapses via androgen specific mechanisms (Leranth et al., 2004a, Leranth et al., 2003). A reasonable interpretation of this finding may be that androgens regulate CA1 spine synapse density through androgen receptor-dependent mechanisms. In the hippocampus, particularly in the CA1 subfield, there is a high level of androgen receptor expression both at nuclear (Kritzer, 2004, Sar et al., 1990, Simerly et

Concluding remarks on potential clinical implications

We have just begun to recognize that neuroplasticity, particularly hippocampal synaptic remodeling, is involved in the neuropathology of a set of disorders that currently represent the highest burden for society, such as neurodegenerative diseases, schizophrenia, depression, and stress. Because the hippocampus is commonly involved, it is not surprising that the vast majority of these patients all suffer from cognitive impairment, memory dysfunction, affective problems, as well as an abnormal

Acknowledgments

This work was supported by NIH grants MH060858 (CL), NS042644 (CL), MH074021 (TH), a 2007 NARSAD Young Investigator Award (TH), as well as by a grant from the Hungarian National Office for Research and Technology RET-08/04.

References (85)

  • KasaiH. et al.

    Structure–stability–function relationships of dendritic spines

    Trends Neurosci.

    (2003)
  • KeenanP.A. et al.

    Prefrontal cortex as the site of estrogen's effect on cognition

    Psychoneuroendocrinology

    (2001)
  • KolbB.

    Functions of the frontal cortex of the rat: a comparative review

    Brain Res.

    (1984)
  • LeranthC. et al.

    Hormonal regulation of hippocampal spine synapse density involves subcortical mediation

    Neuroscience

    (2000)
  • LewisC. et al.

    Estrogen-induction of dendritic spines in ventromedial hypothalamus and hippocampus: effects of neonatal aromatase blockade and adult GDX

    Brain Res. Dev. Brain Res.

    (1995)
  • MacLuskyN.J. et al.

    Estrogen formation in the mammalian brain: possible role of aromatase in sexual differentiation of the hippocampus and neocortex

    Steroids

    (1987)
  • McEwenB.S. et al.

    Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain

    Exp. Gerontol.

    (1994)
  • NaessO.

    Characterization of the androgen receptors in the hypothalamus, preoptic area and brain cortex of the rat

    Steroids

    (1976)
  • ParduczA. et al.

    Synaptic remodeling induced by gonadal hormones: neuronal plasticity as a mediator of neuroendocrine and behavioral responses to steroids

    Neuroscience

    (2006)
  • RichieJ.P.

    Anti-androgens and other hormonal therapies for prostate cancer

    Urology

    (1999)
  • ScheffS.W. et al.

    Synaptic pathology in Alzheimer's disease: a review of ultrastructural studies

    Neurobiol. Aging

    (2003)
  • SteinerM. et al.

    Hormones and mood: from menarche to menopause and beyond

    J. Affect. Disord.

    (2003)
  • SunderlandT. et al.

    Reduced plasma dehydroepiandrosterone concentrations in Alzheimer's disease

    Lancet

    (1989)
  • TaboriN.E. et al.

    Ultrastructural evidence that androgen receptors are located at extranuclear sites in the rat hippocampal formation

    Neuroscience

    (2005)
  • WallaceM. et al.

    Ovariectomized rats show decreased recognition memory and spine density in the hippocampus and prefrontal cortex

    Brain Res.

    (2006)
  • YarbroughW.G. et al.

    A single base mutation in the androgen receptor gene causes androgen insensitivity in the testicular feminized rat

    J. Biol. Chem.

    (1990)
  • AhmadianiA. et al.

    Anticonvulsant effect of flutamide on seizures induced by pentylenetetrazole: involvement of benzodiazepine receptors

    Epilepsia

    (2003)
  • AlmeidaO.P.

    Sex playing with the mind. Effects of oestrogen and testosterone on mood and cognition

    Arq. Neuro-Psiquiatr.

    (1999)
  • BardinC.W. et al.

    Testosterone: a major determinant of extragenital sexual dimorphism

    Science

    (1981)
  • Barrett-ConnorE. et al.

    Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study

    J. Am. Geriatr. Soc.

    (1999)
  • DelhezM. et al.

    Testosterone and depression in men aged over 50 years. Andropause and psychopathology: minimal systemic work-up

    Ann. Endocrinol. (Paris)

    (2003)
  • DonCarlosL.L. et al.

    Androgen receptor immunoreactivity in forebrain axons and dendrites in the rat

    Endocrinology

    (2003)
  • FreundT.F. et al.

    GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus

    Nature

    (1988)
  • FriedmanG.

    The effects of estrogen on short-term memory in genetic men

    J. Am. Med. Dir. Assoc.

    (2000)
  • GeinismanY. et al.

    Associative learning elicits the formation of multiple-synapse boutons

    J. Neurosci.

    (2001)
  • GouldE. et al.

    Gonadal steroids regulate dendritic spine density in hippocampal pyramidal cells in adulthood

    J. Neurosci.

    (1990)
  • HajszanT. et al.

    Neurologic links between epilepsy and depression in women: is hippocampal neuroplasticity the key?

    Neurology

    (2006)
  • HajszanT. et al.

    Effects of androgens and estradiol on spine synapse formation in the prefrontal cortex of normal and testicular feminization mutant male rats

    Endocrinology

    (2007)
  • HajszanT. et al.

    Short-term treatment with the antidepressant fluoxetine triggers pyramidal dendritic spine synapse formation in rat hippocampus

    Eur. J. Neurosci.

    (2005)
  • HajszanT. et al.

    Dehydroepiandrosterone increases hippocampal spine synapse density in ovariectomized female rats

    Endocrinology

    (2004)
  • HaoJ. et al.

    Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex

    Proc. Natl. Acad. Sci. U. S. A.

    (2007)
  • HaoJ. et al.

    Estrogen alters spine number and morphology in prefrontal cortex of aged female rhesus monkeys

    J. Neurosci.

    (2006)
  • Cited by (0)

    View full text