How does GABA behave in the intact brain?Admin

Q: Dr. Zilberter,

In your post at brainfuels.com, you cited several researchers and the closing phrase was: “The work undermined the role of depolarizing GABA”, commented Dr. Jean-Marc Goaillard from the Mediterranean University in Marseille”.

First, does depolarizing equals inhibitory? Second, I just wondered:  why nobody directly measured GABA properties in the whole brain, in natural conditions? Wouldn’t it be the final proof of how GABA behaves in its natural environment?

Thank you,

Theo

A: Dear Theo,

Depolarization of neuronal membrane is a change making it more electrically positive, or less negative. In neurons it may result in an action potential if the depolarization is larger than certain threshold. If this event repeats on a regular basis, the neuron or a network of connected neurons becomes more active (more frequently generating action potentials). In the case of GABA, the primary inhibitory neurotransmitter, depolarization means that it is in a less inhibitory state often failing to prevent the excitatory transmitter(s) from hyperactivity, which in clinical sense can mean seizures.

Hyper-polarization, on the other hand, inhibits the occurrence of an action potential, in his respect, when GABA is inhibitory, the odds of hyperactivity decrease. Now, regarding your second (excellent!) question, I can give you a reference to a PhD thesis, where the student reported this exact result (1). He investigated GABA properties in  whole mice (in vivo) and demonstrated that GABA was always inhibitory – unlike experimental results obtained on brain slices where GABA was depolarizing in young animals. Since in this project, researchers (the student, S. Rheims and his supervisor, Dr. Y. Zilberter) were interested in ketone bodies as the usual suspect when it comes to the anti-epileptic effects of the ketogenic diet, they chemically blocked the ketogenesis preventing ketone bodies from being produced to work as brain fuel.
In this condition, GABA behaved pretty much as it does in brain slices. This and the in toto (see footnote) experiment results, tell us that the “excitatory GABA” is, perhaps: 1) result of experimental limitation of the brain slice preparation; 2) GABA action depend on metabolic status of not only brain slice but also of a whole intact animal in a bad metabolic condition.

Footnote. Since this Q&A, I posted results on in toto experiments (2, 3, 4), where GABA was also inhibitory in the preparation of a whole hippocampus of immature animals : Studies of GABA action: in vivo, in toto, and in vitro

Sources:

1. S. Rheims; PhD Thesis,2008. Faculté des Sciences de Luminy Ecole Doctorale de la Vie et de la Santé. Initiation et modulation des oscillations physiologiques et pathologiques dans le neocortex immature: role de la transmission GABAergique.

2. Wong, T., et al. (2005) Postnatal development of intrinsic
GABAergic rhythms in mouse hippocampus. Neuroscience 134, 107-120

3. Derchansky, M., et al. (2008) Transition to seizures in the
isolated immature mouse hippocampus: a switch from dominant phasic
inhibition to dominant phasic excitation. J Physiol 586, 477-494

4. Dzhala V et. al., Progressive NKCC1-Dependent Neuronal Chloride Accumulation during Neonatal Seizures The Journal of Neuroscience, (2010) 30(35):11745–11761 • 11745