"In the mammalian brain, the neocortex is the site where sensory information is integrated into complex cognitive functions. This is accomplished by the activity of both principal glutamatergic neurons and locally-projecting inhibitory GABAergic interneurons, interconnected in complex networks. Inhibitory neurons play several key roles in neocortical function. For example, they shape sensory receptive fields and drive several high frequency network oscillations. On the other hand, defects in their function can lead to devastating diseases, such as epilepsy and schizophrenia. Cortical interneurons represent a highly heterogeneous cell population. Understanding the specific role of each interneuron subtype within cortical microcircuits is still a crucial open question. We have examined properties of two major functional interneuron subclasses in neocortical layer V: fast-spiking (FS) and low-threshold spiking (LTS) cells. Our previous data indicate that each group expresses a novel form of self inhibition, namely autaptic inhibitory transmission in FS cells and an endocannabinoid-mediated slow self inhibition in LTS interneurons. In this proposal we will address three major questions relevant to self-inhibition of neocortical interneurons: 1) What is the role of FS cell autapses in coordinating fast network synchrony? 2) What are the molecular mechanisms underlying autaptic asynchronous release, prolonging FS cell self-inhibition by several seconds, and what is its relevance during physiological and pathological network activities? 3) What are the induction mechanisms, the molecular players involved and the functional roles within cortical microcircuits of the endocannabinoid-mediated long-lasting self-inhibition in LTS interneurons? Results of these experiments will lead to a better understanding of GABAergic interneuron regulation of neocortical excitability, relevant to both normal and pathological cortical function."