• Activity-dependent short-term depression of inhibitory synaptic currents in the hippocampus

      Whittington, Kevin C.; Alger, Bradley Eugene (2010)
      An understanding of the regulation of GABAergic synaptic inhibition is important because of its influence on neuronal excitability, synaptic plasticity, and disease processes in the central nervous system. Aberrant inhibition is believed to be the cause of pathophysiological processes, such as epilepsy and mood disorders (e.g. anxiety). I seek to determine what regulates inhibitory transmission at short time scales (milliseconds - minutes) in the hippocampus, the structure that provides a cognitive map of the physical environment and, in addition, is the locus of explicit memory formation. I use electrophysiological and pharmacological tools to study inhibitory transmission at certain interneuron-pyramidal neuron synapses in the CA1 field of the rat hippocampus. Certain interneurons, those that contain cholecystokinin, also express the presynaptic cannabinoid receptor (CB1) as well as the GABAB autoreceptor, both key mediators of presynaptic inhibition. Hippocampal interneurons can fire in rhythmic, brief bursts. However, the roles of endogenous cannabinoids (endocannabinoids; eCBs) and GABAB autoreceptors in regulating inhibitory postsynaptic currents (IPSCs) elicited by such bursts has not been described. The fundamental hypothesis is that certain features of the short-term depression induced by these bursts are mediated by eCBs and others by GABA acting on GABAB autoreceptors. I find that eCB-mediated depression of pyramidal cell IPSCs develops slowly (tau ~ 30 s). IPSC depression mediated by the GABAB autoreceptor occurs in parallel with the eCB-mediated depression, but it is restricted to the time domain of hundreds of milliseconds (tau ~ 100 ms). Interestingly, although CB1 and GABAB receptors are expressed on the same nerve terminals, have the same effector (the Gi/o G protein), and the same molecular targets (Ca2+ and K+ channels), they reduce inhibitory transmission via non-interacting and distinct mechanisms. I also discovered that eCBs are released from cells via a novel mechanism. I conclude that a new form of short-term depression mediated by eCBs is present at certain inhibitory synapses of the hippocampus, and may help understand the functions of hippocampal neuronal circuits.