Timing in the cerebellum: Duration of inhibition and mechanisms of control

Abstract

Inhibitory neurotransmission by GABA_A receptors powerfully regulates neuronal activity. Previous studies independently observed that a number of GABA_A receptor subunits are expressed differently through brain development and that synaptic inhibition undergoes certain developmental changes. I extended these studies to trace a temporal pattern of correlated changes of inhibitory synaptic function and the expression of distinct GABA _A receptor subunits by using a combination of electrophysiological, immunocytochemical and pharmacological tools. Furthermore, I observed deviations from normal development at the synapses in cerebellar granule cells of mice lacking the alpha 1 subunit of the GABA_A receptor. In particular, I found evidence that the expression of alpha 2/alpha 3 subunits underlies increased duration of synaptic currents and may explain the lack of behavioral phenotype in these mice. However, inhibitory neurotransmission is not limited to synapses and, despite blooming interest in tonic nonsynaptic inhibition, it remained uninvestigated in the alpha 1 knock-out model. I identified an increase in tonic inhibitory tone at Golgi-granule cell synapse in the cerebellum of the alpha I knock-out mice. A detailed electrophysiological and biochemical investigation of the possible sources of such an increase revealed a surprising role for GABA uptake transporters, rather than GABA _A receptors themselves, as mediators of increased tonic inhibition. Thus, intricate dynamics between the components of synaptic and non-synaptic GABA-mediated neurotransmission influence the nature of inhibition in the alpha 1 knock-out mice, but likely also, in their wild-type counterparts. I conclude with a study showing that the combined action of the two types of inhibition may have an unexpected behavioral application in mediating the neuronal effects of pheromones.