In neo-nates benzodiazepines are not very effective in treating seizures, and this is probably because of the changing role you've mentioned of GABA at different stages in neurodevelopment; the mechanisms underlying this developmental shift in action are described in the article you have linked to.

See also;

http://www.ncbi.nlm.nih.gov/pubmed/1282225

http://www.ncbi.nlm.nih.gov/books/NBK98206/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691543/

Dear Karlo,

GABA is not an excitatory transmitter. What happens is that during early development due to delayed expression of chloride cotransporters, the intracellular concentration of chloride is higher inside the cell than the extra cellular environment. Therefore when the GABA-A receptors activated and the channel opens Cl- ions move out of the cytoplasm, result in membrane depolarization. With development, the intracellular Cl- concentrations drop with increased activity of chloride co-transporters, and Activation of GABA-A channels results in influx of chloride and hyperpolarizes the cell.

I believe this depolarising effect of GABA varies among neuronal populations and depends on developmental stage. For example in respiratory motoneurons, GABA is already inhibitory at the time of the birth. I have recorded this Inhibitory post-synaptic currents/potentials from the soma and dendrites. For details see my following publications. My results are based on research in rodents. I am not sure if anybody knows or shown depolarizing effect of GABA-A receptor activation in human neurons? If GABA is depolarizing in newborn children in neural pathways that are involved in epileptic seizures, then one would expect that the agonists of GABA-A receptors such as benzodiazepines to make the outcome worse, and increase the epileptic seizures. This means that use of benzodiazepines in treatment of epilepsy in newborns may be counter active.

best wishes, Refik

Article Emerging Roles of Filopodia and Dendritic Spines in Motoneur...

Article Glycinergic Neurotransmission: A Potent Regulator of Embryon...

In the immature or the distressed brain (e.g. after cardiac arrest) arousal effects of GABAergic substances have been described, most likely because of an excitatory effect on a pallido-thalamic pathway.

The idea of excitatory GABA during development has been challenged, as intracellular Cl- concentration is very dependent on experimental procedures (oxygenation, energy substrates, etc), and excitatory GABA was mostly reported in slice studies. Two recent in-vivo studies have directly shown GABA to be inhibitory in neonates: 

1. Kirmse, K., Kummer, M., Kovalchuk, Y., Witte, O. W., Garaschuk, O., & Holthoff, K. (2015). GABA depolarizes immature neurons and inhibits network activity in the neonatal neocortex in vivo. Nature Communications, 6, 7750. http://doi.org/10.1038/ncomms8750

2. Valeeva, G., Tressard, T., Mukhtarov, M., Baude, A., & Khazipov, R. (2016). An Optogenetic Approach for Investigation of Excitatory and Inhibitory Network GABA Actions in Mice Expressing Channelrhodopsin-2 in GABAergic Neurons. Journal of Neuroscience, 36(22), 5961–5973. http://doi.org/10.1523/JNEUROSCI.3482-15.2016

See also:

Zilberter, M. (2016). Reality of Inhibitory GABA in Neonatal Brain: Time to Rewrite the Textbooks? Journal of Neuroscience, 36(40), 10242–10244. http://doi.org/10.1523/JNEUROSCI.2270-16.2016

Bregestovski, P., & Bernard, C. (2012). Excitatory GABA: How a Correct Observation May Turn Out to be an Experimental Artifact. Frontiers in Pharmacology, 3, 65. http://doi.org/10.3389/fphar.2012.00065

Dear Mischa,

Thank you for contribution.

Then which side would you take in this contradictory situation. Since, clinically it is observed that GABA agonists may exacerbate the seizure in a vey young child, but on the other hand also provide relief (explained by saturation/depletion of chloride gradient).

EDIT:

Neonatal Seizures: An Update on Mechanisms and Management

Frances E. Jensen

Clin Perinatol. Author manuscript; available in PMC 2010 Dec 1.

Published in final edited form as: Clin Perinatol. 2009 Dec; 36(4): 881. doi: 10.1016/j.clp.2009.08.001 (in the link, I Know it's from 2010 - but what it states is the KCC2 is absent in 'young' brains)

Regards,

K

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818833/

Well, one possibility involves the fact that intracellular chloride is regulated by energy metabolism, and one has to distinguish between healthy and pathological brain states. We will soon publish two papers, one showing that partially inhibiting glycolysis by 2-DG results in depolarization of both Em and Egaba in slices and results in epilepsy in-vivo; at the same time, in the second study we found that seizures themselves result in a long-lasting inhibition of glycolysis and increased excitability (with GABA most likely also shifting towards excitatory). So, if the developing brain has already entered an epileptic state, it is likely that GABA has become pathologically excitatory, with the network in a downward spiral of epileptigenesis. Therefore, GABA agonists would only exascerbate the condition. 

Thanks for sharing. Have you considered altered metabolism in epilepsy in regards to beneficial responses seen with ketogenic diet?

Indeed we have :) Hopefully the article will be out soon. The common misconception about KD is that reduced glycolysis during ketosis is a form of energy inhibition leading to activation of Katp channels (for example), reducing excitability. But the truth is, ATP levels do not change under KD. What most likely happens is that ketone body metabolism bypasses disrupted glycolysis, normalizing energy levels and downstream neuronal function.