The Epilepsy Currents journal, Volume 10, Issue 5, pages 128-30, September/October 2010, published an article titled "Another Look at Early GABAergic Neurotransmission: Maybe It�s Not So Exciting After All!" by Jong M. Rho MD.
Pros and Cons of reconsidering the excitatory GABA dogma according to Dr Rho, in direct quotes *
PROs:
- "Collectively, these studies cast doubt on the biological relevance of GABA-induced depolarization as evidenced by a multitude of cellular electrophysiological studies." [1, 2]
- "Certainly, these authors make a compelling case for a thoughtful re-examination of the time-honored use of ACSF formulations that solely employ glucose as an energy substrate." **
- "If the observations of Rheims et al. and Holmgren and colleagues are ultimately validated, then a couple of generations of in vitro studies are likely to be at risk for relegation to the murky domain of artifact."
- "Intriguing as their findings are, the authors have not yet firmly established a mechanism for their general observation ofmetabolic substrate-induced reversal of GABA excitation, despite preliminary evidence invoking the bicarbonate-chloride exchanger."
- "Although Rheims et al. and Holmgren and colleagues indicate that their results may be similar to the mechanism of ketogenic action, this link remains speculative at best."
- "Whether GABA-evoked depolarization is merely a developmental aberration that is compensated for by differential and age-dependent utilization of energy substrates or whether it is still a fundamental physiological phenomenon important for neuronal maturation, and possibly seizure genesis, remains unclear." ***
- - - - -
* all six points are direct quotations of Dr Rho selected to demonstrate his opinion of the papers (1, 2)
** see recent review: Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis
*** There's a growing body of evidence in favor the first part of the statement and against its second part showing that the excitatory GABA phenomenon exists only in certain conditions: either brain slices supported by standard ACSF or, if in vivo, during blockade of ketogenesis (3). In healthy immature animals in vivo (3, 4) , as well as in hippocampal preparations in toto (5-7), GABA is shown to always be inhibitory.
References
1. GABA Action in Immature Neocortical Neurons Directly Depends on the Availability of Ketone Bodies. Rheims S, Holmgren CD, Chazal G,Mulder J, Harkany T, Zilberter T, Zilberter Y. J Neurochem 2009;110(4):1330-1338
2. Energy Substrate Availability as a Determinant of Neuronal Resting Potential, GABA Signaling and Spontaneous Network Activity in the Neonatal Cortex In Vitro. Holmgren CD,MukhtarovM,Malkov AE, Popova IY, Bregestovski P, Zilberter Y. J Neurochem 2010;112(4):900-912
3. Rheims S., PhD thesis, Universite de la Mediterranee, 2008
4. Bremner L, Fitzgerald M & Baccei M. (2006). Functional GABAA-Receptor-Mediated Inhibition in the Neonatal Dorsal Horn. J Neurophysiol 95, 3893-3897
5. Wong, T., et al. (2005) Postnatal development of intrinsic GABAergic rhythms in mouse hippocampus. Neuroscience 134, 107-120
6. 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
7. Dzhala V et. al., Progressive NKCC1-Dependent Neuronal Chloride Accumulation during Neonatal Seizures The Journal of Neuroscience, (2010) 30(35):11745-11761 � 11745
This is a very good review of these two articles on GABA-action. I also liked your comments to the point #3 of CONs. Indeed, the situation clearly changes fast and for me personally, there�s no doubts that "GABA-evoked depolarization is merely a developmental aberration that is compensated for by differential and age-dependent utilization of energy substrates" - since this is how it behaves in natural conditions (more or less natural I mean), in toto and in vivo!
Comment by Deb - October 7, 2010 @ 3:59 am
Way to go! I liked the review and how you presented it here.
Paulina
Comment by Paulina - October 7, 2010 @ 6:26 am
Tanya,
I just wanted to ask you my next questions at allexperts but saw you on vacation. I�m just wondering what�s being left of the excitatory GABA theory after these new developments? Do yo have anything up your sleeve
? Keep us informed and thank you1
Ingrid
Comment by Ingrid - October 12, 2010 @ 8:33 am
Here�s some more:
Whole cell patch recording from lamina II neurons in spinal cord slices has shown that inhibitory transmission in the spinal dorsal horn in early postnatal life is dominated by GABA-mediated currents, the majority of which are inhibitory from birth (1, 2)
1. Bremner L, Fitzgerald M & Baccei M. (2006). Functional GABAA-Receptor- Mediated Inhibition in the Neonatal Dorsal Horn. J Neurophysiol 95, 3893- 3897.
2. Baccei ML & Fitzgerald M. (2004). Development of GABAergic and Glycinergic Transmission in the Neonatal Rat Dorsal Horn. J Neurosci 24, 4749-4757.
Comment by admin - November 18, 2010 @ 6:32 am