Modulation of cortical slow oscillatory rhythm by GABAB receptors: an experimental and computational study

Abstract

Slow wave oscillations (SWO) dominate cortical activity during deep sleep, anesthesia and in some brain lesions. SWO consist of Up states or periods of activity interspersed with Down states or periods of silence. The rhythmicity expressed during SWO integrates neuronal and connectivity properties of the network and it is often altered in neurological pathological conditions. Different mechanisms have been proposed to drive the transitions between Up and Down states, in particular, adaptation mechanisms have been proposed to contribute to the Up-to-Down transition. Synaptic inhibition, and specially GABAB receptors, have also been proposed to have a role in the termination of Up states. The interplay between these two potential mechanisms, adaptation and inhibition, is not well understood and the role of slow inhibition is not yet clear regarding the full cycle of the slow oscillatory rhythm. Here we contribute to its understanding by combining experimental and computational techniques. GABAB receptors-blockade not only elongated Up states, but also affected the subsequent Down states, and thus the whole cycle of the oscillations. Furthermore, while adaptation tends to yield a rather regular behavior, GABAB receptors-blockade decreased the variability of the sequence of Up and Down states. Interestingly, variability changes could be accomplished in two different ways: either accompanied by a shortening or by a lengthening of the duration of the Down state. Even when the most common observation is the lengthening of the Down states, both changes are expressed experimentally and also in numerical simulations. Our simulations suggest that the sluggishness of GABAB receptors to follow the excitatory fluctuations of the cortical network can explain these different network dynamics modulated by GABAB receptors.