Acetylcholine (ACh) release from the medial septum-diagonal band of Broca (MS-DBB) to the hippocampus profoundly alters cellular excitability, network synchronization, and behavioral state. Deficits in cholinergic function are associated with memory impairments, such as in Alzheimer’s disease, while excessive cholinergic activity, such as in organophosphate exposure, can induce

seizures and lead to neuronal death. ACh has diverse pre- and postsynaptic targets onto both glutamatergic and GABAergic cell populations in the hippocampus. Recent evidence has emerged indicating that the actions of ACh can be highly specific, altering the excitability of distinct GABAergic circuits in a cell type-specific manner. Although cholinergic activation of interneurons and

principal cells are thought to generate theta oscillations, molecular and cellular details regarding cholinergic transmission onto specific hippocampal target cells remain poorly understood. Using a combination of immunocytochemical, electrophysiological, transgenic mouse, optogenetic, and computational modeling approaches, we are currently defining the relationship between the spatial

localization of MS-DBB afferents and the physiological consequence of cell typespecific cholinergic modulation, with the ultimate goal of developing mathematical models of cell type-specific cholinergic transmission. Fast spiking parvalbumincontaining (PV+) neurons will be discussed in particular. Muscarinic acetylcholine receptor (mAChR) activation generates a large depolarizing current in PV basket cells that is absent in global M1 mAChR KO mice (Cea del Rio et al. 2010). We have now selectively ablated M1 mAChRs from PV+ cells by crossing PVCRE+/+

and floxed M1+/+ mice. The resulting PV-Cre/fM1 mice showed reduced frequency and amplitude of spontaneous inhibitory postsynaptic currents compared to their wild type (WT) littermates, suggesting that tonic activation of M1 mAChRs on PV+ cells is important for normal GABAergic transmission. In behavioral tasks, while PV-CRE/fM1 mice exhibited deficits in working and

recognition memory, normal locomotion and spatial memory remained intact. Finally, we examined PV-CRE/fM1 mice in the development of pilocarpineinduced seizures. Following pilocarpine administration, a less severe phenotype was observed in PV-CRE/fM1 than WT, suggesting that M1 mAChRs on PV cells contributes to pilocarpine-induced epileptogenesis in WT mice. We conclude that cholinergic receptors on inhibitory interneurons play key roles in normal and pathophysiological disease processes.