ReviewRole of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas
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.
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