Related Experiment Videos
Slow death of postnatal hippocampal neurons by GABA(A) receptor overactivation
1Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
Neurotransmitters can have both toxic and trophic functions in addition to their role in neural signaling. Surprisingly, chronic blockade of GABA(A) receptor activity for 5-8 d in vitro enhanced survival of hippocampal neurons, suggesting that GABA(A) receptor overactivation may be neurotoxic. Potentiating GABA(A) receptor activity by chronic treatment with the endogenous neurosteroid (3alpha,5alpha)-3-hydroxypregnan-20-one caused massive cell loss over 1 week in culture. Other potentiators of GABA(A) receptors, including benzodiazepines, mimicked the cell loss, suggesting that potentiating endogenous GABA activity is sufficient to produce neuronal death. Neurosteroid-treated neurons had lower resting intracellular calcium levels than control cells and produced smaller calcium rises in response to depolarizing challenges. Manipulating intracellular calcium levels with chronic elevated extracellular potassium or with the calcium channel agonist Bay K 8644 protected neurons. The results may have implications for the mechanisms of programmed cell death in the developing CNS as well as implications for the long-term consequences of chronic GABAmimetic drug use during development.
Insights
Overactivating GABA(A) receptors with neurosteroids or benzodiazepines causes hippocampal neuron death. Manipulating calcium levels can protect neurons, suggesting implications for neurodevelopmental disorders and drug use.
Area of Science:
- Neuroscience
- Cell Biology
- Neuropharmacology
Background:
- Neurotransmitters like GABA have complex roles, including potential neurotoxicity.
- Chronic GABA(A) receptor blockade surprisingly enhanced neuronal survival in vitro.
- This suggests that GABA(A) receptor overactivation might be neurotoxic.
Purpose of the Study:
- To investigate the neurotoxic potential of GABA(A) receptor overactivation.
- To explore the role of intracellular calcium in GABAergic neurotoxicity.
- To assess the impact of chronic GABAmimetic drug exposure on neuronal survival.
Main Methods:
- Chronic treatment of hippocampal neurons with GABA(A) receptor potentiators (neurosteroids, benzodiazepines).
- Assessment of neuronal survival and cell loss in vitro.
- Measurement of intracellular calcium levels under various conditions.
- Neuroprotection experiments using elevated extracellular potassium and calcium channel agonists.
Main Results:
- Chronic potentiation of GABA(A) receptor activity led to significant neuronal cell loss.
- Neurosteroid and benzodiazepine treatments mimicked this cell death.
- Neurons exposed to GABAergic potentiators exhibited reduced resting intracellular calcium and smaller calcium responses.
- Elevated extracellular potassium and calcium channel agonists conferred neuroprotection.
Conclusions:
- Overactivation of GABA(A) receptors is neurotoxic, contrary to the neuroprotective effects of receptor blockade.
- Intracellular calcium homeostasis plays a critical role in mediating GABAergic neurotoxicity.
- Findings have implications for understanding programmed cell death in the developing central nervous system (CNS) and the effects of chronic GABAmimetic drug use.