I’ve written previously about the dual excitatory-inhibitory roles GABA plays during development and adulthood. Interestingly, when it comes to many neurodevelopmental disorders, including autism and epilepsy, we keep revisiting this topic again and again. Why is GABA’s dual role in the brain so important throughout the lifespan?
It turns out that even though neuroscientists nowadays seem more aware that GABA plays an excitatory role during the prenatal and early neonatal periods helping to promote cell proliferation, growth, and maturation, many may still not be aware that even in adulthood GABA is primed to become less inhibitory at almost a moment’s notice in reaction to stress. And with prolonged exposure to certain types of stress, GABA can even revert to it’s immature excitatory nature.
Because the GABA receptors control the gating of chloride into and out of the cell, a cell’s reaction to GABA docking on its receptor depends on how much of the negatively-charged chloride is inside compared to outside the cell. In immature neurons, more chloride resides within the cell and thus when GABA receptor activation causes chloride channels to open, chloride escapes into the extracellular space, increasing the positive charge of the neuron and lowering the stimulus threshold at which that neuron can fire. In essence, excitatory GABA gives a pyramidal neuron an itchy trigger finger.
Wake et al. (2007) discovered that when a mature neuron is placed under stress, either through oxidative stress, seizure activity, or hyperexcitability, the chloride exporter, KCC2, is rapidly dephosphorylated, quashing its chloride-exporting activities. In addition, though it’s normally expressed at the surface of the cell, neuronal stress causes KCC2 to be transported away from the surface where it serves its exporting function. All of these reactions, in all three scenarios of cell stress, occurs within 1-2 hours of the event. If the stress is prolonged, then within 6-9 hours the absolute levels of KCC2 expression are decreased, suggesting that not only is it being more rapidly degraded but that expression of the KCC2 gene, SLC12A5, has been suppressed.
Image from Wake et al. (2007) showing the localizations of KCC2 (red) in control (upper panels) and hydrogen peroxide-stressed neurons (lower panels). Note that there is comparatively less red KCC2 staining at the cell surface in the stressed cells.
While Wake et al. found that short-term neuronal stress didn’t shift GABA to an entirely excitatory stimulus, stress did lead to decreases in the strength of GABA inhibition, which ultimately lower the stimulus threshold that excitatory pyramidal neurons must reach in order to fire, i.e., itchy trigger finger. However, prolonged neuronal stress, such as can be seen in some epilepsies or traumatic injury, can ultimately lead to a regression in GABA’s function from inhibitory to fully excitatory [1, 2].
Since our brains are subject to all kinds of stressors, whether it’s the anxiety from a long hard day at work, the death of a loved one, the ravages of war, or a traumatic brain injury, the fact that these stressors have physical consequences on the health of neurons means that our brains must have a way to grow, break down, and repair connections. In order to do that, a neuron needs a little extra stimulation to promote those processes and the phosphorylation and downregulation of KCC2, alongside other related players, is just the protein to do it.
Therefore, when we see variations in KCC2 expression in the brains of people with epilepsy, it suggests that part of the pathology of the condition, despite its heterogeneity, may involve processes of growth and repair. (The same is probably also true for autism given its successful treatment of target symptoms with drugs that reduce internal chloride concentrations, but more work is still needed in this area of research.) With both epilepsy and autism, it’s hard to say whether the defects lay originally with growth/repair mechanisms or whether it’s a snowball effect of over-excitation leading to injury, leading to repair and further hyperexcitability, but in either case excitation becomes part and parcel of these conditions’ pathologies. Yet that understanding, ironically, offers us a means for treatment and intervention.
