Taken together, ACh modulation of inhibition consists of two opposing components, simultaneously enhancing di-synaptic inhibition by nAChRs while suppressing GABAergic IPSCs through CB1 signaling. These two mechanisms may work in concert to provide two independent avenues of modulation. Nicotinic receptors exist in fast spiking interneurons of striatum and not in MSNs. Conversely, CB1 receptors are richly expressed in MSNs, but fast spiking interneurons have been shown to be insensitive to CB1 signaling in cortex and hippocampus [52], However, some fast-spiking interneurons in the striatum are shown to be modulated by CB1 signaling [53]. Therefore, modulation of inhibition by nAChR may only contribute to direct regulation in feed-forward inhibition, while modulation by mAChR/CB1 signaling provide a feed-back component that target both FS-MSN feedforward and MSN-MSN collateral inhibition. These two very different forms of modulation differ in both their temporal scale and their cell type specificity and hence generate different epochs of inhibition that govern the spiking output of MSNs.
