Dynamic changes in GABA action: Implications in epilepsy research

Roustem KhazipovThe excitatory and inhibitory actions regulated by neurotransmitters are responsible for brain activity. Glutamic acid mediates excitatory actions while GABA is inhibitory. However it has been known for nearly two decades that during development, GABA exerts a depolarizing action on immature neurons. However, at the network level the effects of GABA are complex involving both excitatory and inhibitory actions.

A group of researchers from Kazan Federal University, Russia and Aix-Marseille University, France, has shown that the actions of GABA critically depend on the network state. They have found that although GABA depolarizes neurons at rest and at the onset of population bursts, it transiently becomes hyperpolarizing at the peak of the population bursts. These dynamic changes in GABA actions enable GABAergic interneurons not only to initiate the network discharge but also to control excitation to prevent epileptiform synchronization. Losing inhibitory and gaining excitatory action by GABA during epilepsy could contribute to the pathogenesis.

They characterized the dynamics of synaptic currents mediated by GABA(A) and glutamate receptors through an estimation of the changes in their conductance and driving forces in neonatal rat CA3 pyramidal cells during GDPs. They found that depolarizing GABAergic and glutamatergic currents act in synergy at the GDPs' onset. However, during the peak of the population discharge, the inward synaptic current was essentially mediated by glutamate receptors whereas GABA currents transiently switched their direction from depolarizing to hyperpolarizing as a result of neuronal depolarization above the GABA(A) reversal potential.

Thus, the action of GABA on CA3 pyramidal cells dynamically changes during GDPs from excitatory at the GDPs' onset to inhibitory at the GDPs' peak. Dynamic changes in GABA actions occurring during GDPs seem to enable GABAergic interneurons not only to initiate the discharge of pyramidal cells but also to control excitation in the recurrent CA3 network preventing epileptiform synchronization.

According to the research team led by Roustem Khazipov, from Kazan Federal University, Russia the brain appears to be in two states: sleeping and arousal and it switches between them quite rhythmically, e.g. during deep sleep a brain can change its state several times within a second. In their recent study published in Journal of Neuroscience they demonstrate that GABA performs excitatory actions in a "sleep" state in children, and vice versa, inhibitory actions when the brain is aroused. In addition to that, in adult brain GABA switches from inhibition to excitation in epilepsy and other conditions including post traumatic brain injury and ischemia.

The experiments were performed on neonatal rats and mice hippocampus since it relates closely to that of human fetus at the second half of pregnancy period. The findings have potential applications in the treatment of epilepsy, ischemia and brain trauma.

Citation:Khalilov I, Minlebaev M, Mukhtarov M, Khazipov R. Dynamic Changes from Depolarizing to Hyperpolarizing GABAergic Actions during Giant Depolarizing Potentials in the Neonatal Rat Hippocampus. J Neurosci. 2015 Sep 16;35(37):12635-42. doi: 10.1523/JNEUROSCI.1922-15.2015. PubMed PMID: 26377455. Full Text1.13 MB