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Journal of Neuroscience, Vol 15, 5065-5077, Copyright © 1995 by Society for Neuroscience
GABA neurotransmission in the hypothalamus: developmental reversal from Ca2+ elevating to depressing
K Obrietan and AN van den Pol
Department Biological Science, Stanford University, California 94305, USA.
GABA is the primary inhibitory transmitter of the adult hypothalamus,
synthesized by many neurons and found in 50% of the presynaptic boutons.
GABA causes a decrease in Ca2+ in mature hypothalamic neurons in vitro by
depressing cellular activity through opening Cl- channels. Despite the
early expression of GABAA receptors in the embryonic hypothalamus (E15),
the cellular function of GABA in the developing hypothalamus has received
little attention. In the present study the role of GABA in modulating
intracellular Ca2+ in developing hypothalamic neurons was studied with
fura-2 digital imaging. GABA (0.5- 500 microM) applied to embryonic
hypothalamic neurons elicited a dramatic and rapid increase in
intracellular Ca2+ This Ca2+ rise could be completely blocked by the GABAA
antagonist bicuculline (20 microM) and persisted in the presence of
tetrodotoxin (1 microM). The Ca2+ elevation induced by GABA was greater
than that of equimolar concentrations of the excitatory transmitter
glutamate in early development. The number of E15 neurons that responded to
GABA with a Ca2+ rise increased during the first few days of culture,
reaching 78% after 4 d in vitro. The Ca2+ rise was 87% blocked by cadmium
(100 microM) and 85% blocked by nimodipine (1 microM), indicating that the
mechanism of Ca2+ increase was primarily via L-type voltage operated Ca2+
channels. Addition of bicuculline to synaptically coupled cultures caused a
significant decrease in Ca2+ 4-10 d after culturing, indicating
hypothalamic neurons were secreting GABA at an early age of development,
and that sufficient GABA was released to elicit an increase in Ca2+. This
effect was seen even after blocking all glutamatergic activity with
glutamate receptor antagonists. In contrast, GABA elicited no Ca2+ rise in
older neurons (> 18 d in vitro), and the action of bicuculline reversed
and caused a large increase in Ca2+ in spontaneously active neurons.
Similar findings were obtained in cultures enriched in GABAergic neurons
from the suprachiasmatic nucleus. To determine if the Ca2+ stimulating role
of GABA on developing neurons was restricted to the hypothalamus and a few
other regions, or whether it might exist throughout the brain, we examined
the Ca2+ responses in cultured olfactory bulb, cortex, medulla, striatum,
thalamus, hippocampus, and colliculus. The majority (75%) of developing
neurons from each region showed a Ca2+ rise in response to GABA. Together
these data suggest that GABA elevates Ca2+ in developing, but not mature,
neurons from the hypothalamus and all other brain regions
examined.(ABSTRACT TRUNCATED AT 400 WORDS)
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