[Abstract Title]. - Society for Neuroscience

Disclosures: C.L. Wright , None; M.M. McCarthy, None.
Poster
278. Sex Differences I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 278.11/MM4
Topic: E.01.d. Development
Support: NIH MH 52716-010 MMM
Title: Estradiol upregulates SPAK in the developing brain: a possible mechanism for estradiolmediated
enhancement of depolarizing GABA
Authors: B. M. NUGENT 1 , J. M. SCHWARZ 1 , *M. M. MCCARTHY 2,3,1 ;
1 Program in Neurosci., 2 Dept Physiol, 3 Dept Psychiatry, Univ. Maryland Sch. Med., Baltimore,
MD
Abstract: During brain development the normally inhibitory transmitter, γ-Aminobutyric acid
(GABA), exerts an excitatory effect. This is because immature neurons have higher levels of [Cl -
]i relative to [Cl - ]e due to elevated levels of the Na-K-2Cl - co-transporter (NKCC1), which brings
Cl - into the cell, and low expression levels of the K-Cl - co-transporter (KCC2), which removes
Cl - from the cell (Plotkin et al., J Neurobiol 1997:33; Rivera et al., Nature 1999:397).
Consequently, activation of GABAA receptors results in Cl - efflux and membrane depolarization,
resulting in Ca 2+ influx through L-type voltage-gated Ca 2+ channels (Nunez et al., Eur J Neurosci
2005:21). Estradiol is an important regulator of bran development. Our lab has shown that
estradiol enhances GABA-mediated Ca 2+ influx in the neonatal brain and that expression of
NKCC1 is increased in neonatal rats exposed to estradiol. In addition, we have shown that
phosphorylation of the NKCC1 co-transporter is increased in animals treated with estradiol for
the first two days after birth (Perrot-Sinal et al, J Neuroendo 2007:19). NKCC1 activity is
determined by its phosphorylation state, and the Ste20-related proline alanine-rich kinase
(SPAK) has been implicated in regulation of NKCC1 activity (Delpire and Gagnon, Acta Physiol
2006:187). We hypothesized that estradiol might increase the activity of NKCC1 via SPAK
upregulation. To assess changes in SPAK protein levels following estradiol treatment, we
administered 17β-estradiol to female pups on their day of birth and collected hypothalamic and
hippocampal tissue for western blot analysis 6 and 24 hours following hormone administration.
SPAK levels were significantly elevated in neonatal female rat pups following 24 but not 6 hours
of estradiol treatment. This data provides a possible mechanism by which estradiol increases
NKCC1 activity, resulting in increased GABA-mediated neuronal excitation. Supported by: NIH
MH 52716-010 to MMM.