Endocannabinoid signalling is required for estrogen-dependent modulation of inhibitory transmission.

It has long been known that the classic female estrogen, 17β-estradiol (E2), is produced in multiple brain regions including the hypothalamus, hippocampus, as well as sensory areas such as the auditory and visual cortices (McEwen 2002; Woolley 2007; Jeong et al. 2011; Tremere et al. 2011; Pinaud and Tremere 2012). Importantly, this brain-generated E2, distinct from the gonadal hormone, exerts local effects by acting on estrogen receptors that are also expressed in these diverse brain areas. As such, E2 derived in the brain has been shown to play multiple functional roles ranging from sensory processing, reproductive biology and cognitive processes including those supporting learning and memory formation (McEwen 2002; Woolley 2007; McCarthy 2008; Pinaud and Tremere 2012). Notably, many of E2’s effects on neuronal physiology occur rapidly – on a scale of seconds; such rapidity is achieved by E2’s actions on the intrinsic and synaptic communication between neurons and via non-genomic mechanisms (Woolley 2007; Pinaud and Tremere 2012). The mechanistic bases of these actions are not well understood and vary across brain regions. In a recent article published in Neuron, Huang and Woolley (2012) shed significant light on the mechanisms through which E2 modulates synaptic transmission in the adult hippocampus, a brain structure heavily implicated in learning and memory (Huang and Woolley 2012). Specifically, the authors revealed a complex basis for E2’s suppressive effects on peri-somatic inhibitory neurotransmission for pyramidal cells in the hippocampal CA1 subfield. Surprisingly, the effects of E2 on inhibitory transmission were sex specific, occurring in female, but not male, adult rats despite both being subjected to gonadectomization prior to the experiments. Huang and Woolley used hippocampal slices where recordings were obtained from CA1 pyramidal cells. Bath application of E2 was used to explore its impact on inhibitory neurotransmission. Interestingly, E2 largely suppressed the amplitude of both unitary and compound inhibitory post-synaptic currents (IPSCs), similar to findings obtained in other preparations (Tremere et al. 2009). The authors next demonstrated that such modulatory effects of E2 are mediated by the classic intracellular estrogen receptor α (ERα) given that PPT, a selective ERα agonist, produced effects that were identical to E2 on IPSC amplitude and pairedpulse ratios. No effects were detected for ERβ, as activation of this receptor subtype with a selective agonist (DPN) failed to impact E2-sensitive IPSCs. One of the most interesting twists of the Huang and Woolley studies was the finding that activation of ERα alone was not sufficient to alter inhibitory transmission. On CA1 neurons, suppression of inhibition requires both the actions of type-1 cannabinoid receptors (CB1Rs) and metabotropic glutamate receptors, in particular mGluR1-containing receptors (Katona et al. 1999). Huang and Woolley showed, however, that in the absence of functional CB1R signalling, E2 is incapable of suppressing inhibitory responses, thereby establishing that E2’s actions at CA1 neurons depend on cannabinoid signalling through CB1Rs. Specifically, when CB1Rs were blocked, neither E2 nor the ERα agonist affected inhibitory neurotransmission. The reverse scenario was also true: activation of CB1Rs with a selective agonist could largely capture the E2-mediated suppression of IPSCs and paired pulse ratios. In light of the original discovery that E2’s effects were strongly connected to CB1R signalling, a deeper appreciation of this relationship was sought after by the authors. To this end, Huang and Woolley determined how manipulation of either endocannabinoid, 2-arachidonoylglycerol (2-AG) or

Androgen insensitivity syndrome: do trinucleotide repeats in androgen receptor gene have any role? / 亚洲男科学杂志(英文版)

<p><b>AIM</b>To investigate the role of CAG and GGN repeats as genetic background affecting androgen insensitivity syndrome (AIS) phenotype.</p><p><b>METHODS</b>We analyzed lengths of androgen receptor (AR)-CAG and GGN repeats in 69 AIS cases, along with 136 unrelated normal male individuals. The lengths of repeats were analyzed using polymerase chain reaction (PCR) amplification followed by allelic genotyping to determine allele length.</p><p><b>RESULTS</b>Our study revealed significantly shorter mean lengths of CAG repeats in patients (mean 18.25 repeats, range 14-26 repeats) in comparison to the controls (mean 22.57 repeats, range 12-39 repeats) (two-tailed P < 0.0001). GGN repeats, however, did not differ significantly between patients (mean 21.48 repeats) and controls (mean 21.21 repeats) (two-tailed P = 0.474). Among patients' groups, the mean number of CAG repeats in partial androgen insensitivity cases (mean 15.83 repeats) was significantly less than in complete androgen insensitivity cases (mean 19.46 repeats) (two-tailed P < 0.0001).</p><p><b>CONCLUSION</b>The findings suggest that shorter lengths of repeats in the AR gene might act as low penetrance genetic background in varying manifestation of androgen insensitivity.</p>

Phenotypic heterogeneity of mutations in androgen receptor gene / 亚洲男科学杂志(英文版)

Androgen receptor (AR) gene has been extensively studied in diverse clinical conditions. In addition to the point mutations, trinucleotide repeat (CAG and GGN) length polymorphisms have been an additional subject of interest and controversy among geneticists. The polymorphic variations in triplet repeats have been associated with a number of disorders, but at the same time contradictory findings have also been reported. Further, studies on the same disorder in different populations have generated different results. Therefore, combined analysis or review of the published studies has been of much value to extract information on the significance of variations in the gene in various clinical conditions. AR genetics has been reviewed extensively but until now review articles have focused on individual clinical categories such as androgen insensitivity, male infertility, prostate cancer, and so on. We have made the first effort to review most the aspects of AR genetics. The impact of androgens in various disorders and polymorphic variations in the AR gene is the main focus of this review. Additionally, the correlations observed in various studies have been discussed in the light of in vitro evidences available for the effect of AR gene variations on the action of androgens.

A Polymorphic Human Y-Chromosomal G To A Transition Found In India.

We describe a new G to A transition polymorphism, designated Apt, on the human Y chromosome. The A allele chromosomes and the most closely related G allele chromosomes have been found only in India, where they make up about 1.3% of the population. They are found in several different social groups and show considerable microsatellite, minisatellite and major satellite diversity, suggesting that they do not have a recent origin.