Need for negativity: The role of chloride homeostasis and the GABA shift in brain development

Abstract

Our brain is a fascinatingly complex organ comprised of a network of millions of brain cells (neurons), and their connections (synapses). Neurons come in two types: excitatory and inhibitory. When an excitatory neuron is active, it will send positive electrical signals through its excitatory synapses to the next neurons in the network. When an inhibitory neuron is active, it will provide subsequent neurons with negative electrical signals via its inhibitory synapses. All positive and negative signals simultaneously received by a brain cell, determine whether the cell will become active itself and will pass its electrical signals on to the next cells in the network. The development of the brain starts already in the womb. Genes provide the blueprint for the first steps in network formation. In addition, network development is directed by spontaneous neuronal activity generated by excitatory signaling. Excitatory signals allow the fetal neuronal network to grow quickly by stimulating neuronal proliferation, synapse formation and synaptic strengthening. At this time, excitation is mainly provided by a substance called gamma-aminobutyric acid or GABA. Only later on, sensory experiences start affecting the electrical activity in the network. Around the same time, GABA is changing from being excitatory, to inhibitory. Excitation is now provided by another signaling molecule, called glutamate. Inhibition enables the brain to handle an enormous amount of external stimuli in a controlled manner by filtering out irrelevant inputs and only passing on relevant stimuli. The gradual developmental change in the function of GABA from excitation to inhibition is called the GABA shift. During my PhD, I studied the GABA shift in brain slices from mice. Brain development in mice and humans is very similar, though much faster in mice. In comparison: in humans, GABA shifts during the last three months of pregnancy, in mice during the first two weeks after birth. To measure the GABA shift in murine brain slices, we tested a new sensor. We could discern the GABA shift by comparing dozens of neurons in slices of different ages. In addition, we used the sensor to investigate the effect of early life stress on the GABA shift. Stress seemed to delay the GABA shift in young mice. This study underlines the role of experience in brain development, which allows for adaptability, but also leads to vulnerability. We also investigated the consequences of accelerating and delaying the GABA shift. Previous studies have shown that the excitatory GABA promotes synapse formation. Therefore, we expected that a delayed GABA shift would result in an overproduction of synapses. However, this is not what we observed when we manipulated the GABA shift in slices from one week-old mice. We saw that a delayed GABA shift did not affect synapses, but found indirect changes in the neurons’ electrical properties. This work is important for neurodevelopmental disorders such as autism, in which the GABA shift often seems delayed. Our research shows that such a delay affects further brain development.