GABA(A) RECEPTOR AGONISTS REGULATE THE SEXUAL DIFFERENTIATION OF INFANTILE RAT SUBSTANTIA NIGRA RETICULATA NEURONS
Abstract number :
1.067
Submission category :
Year :
2003
Submission ID :
1072
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Aristea S. Galanopoulou, Solomon L. Moshé Neurology, Albert Einstein College of Medicine, Bronx, NY; Neuroscience, Albert Einstein College of Medicine, Bronx, NY; Pediatrics, Albert Einstein College of Medicine, Bronx, NY
The substantia nigra pars reticulata (SNR) is a sexually dimorphic structure involved in movement and seizure control. We have previously shown that at postnatal day 15 (PN15), the GABA(A) receptor agonist muscimol increases intracellular calcium concentration in male but not in female SNR neurons. We hypothesized that muscimol may thus have sex-specific effects on the transcription of calcium-regulated genes in infantile SNR. We studied therefore, in male and female PN15 rat SNR, the in vivo effects of muscimol on the expression of the active phosphorylated form of the transcription factor cAMP responsive element binding protein (phosphoCREB), which regulates calcium-dependent gene transcription. Moreover, we tested the muscimol effects on the mRNA expression of KCC2, a calcium regulated, neuronal specific potassium-chloride cotransporter, which is involved in the functional maturation of GABA(A) receptors.
Male and female PN15 rats were injected with a single subcutaneous injection of muscimol (4[micro]g) or its vehicle. A group of rats was sacrificed one hour after injection, transcardially perfused with paraformaldehyde, and processed with a phosphoCREB specific immunochemistry (Upstate Biotechnology). A second group of rats was sacrificed 4 hours after injection, the brains were snap frozen in dry ice / isomethylbutane and were processed with a KCC2 [ndash] specific, digoxigenin-labeled in situ hybridization. Densitometry of stained cells was performed.
One hour following muscimol injection, phosphoCREB immunoreactivity was increased in male but not in female PN15 SNR neurons. Four hours after muscimol injection, KCC2 mRNA expression increased in male but decreased in female SNR neurons.
Drugs that modulate the activity of GABA(A) receptors can activate calcium-regulated signaling processes and gene transcription in male but not in female PN15 SNR neurons. The distinct translational effects of GABA(A) receptor agonists promote thus the sexual differentiation of the SNR. Through their divergent regulatory effects on KCC2 expression, such drugs may promote the functional maturation of GABA-sensitive, SNR-mediated seizure control in male but inhibit it in female infantile rats.
[Supported by: NIH grants NS45243 (ASG) and NS20253 (SLM), and the Heffer Family Foundation.]