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Volume 17, Number 12, Issue of June 15, 1997 pp. 4785-4799
Copyright ©1997 Society for Neuroscience

GABA Activity Mediating Cytosolic Ca²⁺ Rises in Developing Neurons Is Modulated by cAMP-Dependent Signal Transduction

Received Nov. 1, 1996; revised March 19, 1997; accepted April 3, 1997.

Karl Obrietan and Anthony N. van den Pol

Department of Biological Sciences, Stanford University, Stanford, California 94305, and Department of Neurosurgery, Yale University, School of Medicine, New Haven, Connecticut 06520

In the majority of developing neurons, GABA can exert depolarizing actions, thereby raising neuronal Ca²⁺. Ca²⁺ elevations can have broad consequences during development, inducing gene expression, altering neurite outgrowth and growth cone turning, activating enzyme pathways, and influencing neuronal survival. We used fura-2 and fluo-3 Ca²⁺ digital imaging to assess the effects of inhibiting or activating the cAMP signal transduction pathway on GABA activity mediating Ca²⁺ rises during the early stages of in vitro hypothalamic neural development. Our experiments stemmed from the finding that stimulation of transmitter receptors shown to either activate or inhibit adenylyl cyclase activity caused a rapid decrease in Ca²⁺ rises mediated by synaptically released GABA.

Both the adenylyl cyclase activator forskolin and the inhibitor SQ-22,536 reduced the Ca²⁺ rise elicited by the synaptic release of GABA. Bath application of the membrane-permeable cAMP analogs 8-bromo-cAMP (8-Br-cAMP) or 8-(4-chlorophenylthio)-cAMP (0.2-5 mM) produced a rapid, reversible, dose-dependent inhibition of Ca²⁺ rises triggered by synaptic GABA release. Potentiation of GABAergic activity mediating Ca²⁺ rises was observed in some neurons at relatively low concentrations of the membrane-permeable cAMP analogs (20-50 µM). In the presence of tetrodotoxin (TTX), postsynaptic Ca²⁺ rises triggered by the bath application of GABA were only moderately depressed (13%) by 8-Br-cAMP (1 mM), suggesting that the inhibitory effects of 8-Br-cAMP were largely the result of a presynaptic mechanism.

The protein kinase A (PKA) inhibitors H89 and Rp-3,5-cyclic monophosphothioate triethylamine also caused a large reduction (>70%) in Ca²⁺ rises triggered by synaptic GABA release. Unlike the short-term depression elicited by activation of the cAMP signal transduction pathway, Ca²⁺ depression elicited by PKA inhibition persisted for an extended period (>30 min) after PKA inhibitor washout. Postsynaptic depression of GABA-evoked Ca²⁺ rises triggered by H89 (in the presence of TTX) recovered rapidly, suggesting that the extended depression observed during synaptic GABA release was largely through a presynaptic mechanism. Long-term Ca²⁺ modulation by cAMP-regulating hypothalamic peptides may be mediated through a parallel mechanism.

Together, these results suggest that GABAergic activity mediating Ca²⁺ rises is dependent on ongoing PKA activity that is maintained within a narrow zone for GABA to elicit a maximal Ca²⁺ elevation. Thus, neuromodulator-mediated changes in the cAMP-dependent signal transduction pathway (activation or inhibition) could lead to a substantial decrease in GABA-mediated Ca²⁺ rises during early development.

Key words: mediobasal hypothalamus; calcium; GABA; GABA excitation; protein kinase A; cAMP; development; digital imaging

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