The central nervous system is a crystalline-like structure which is constructed through the repeated assembly of stereotyped circuits. These circuits connect a relatively homogenous population of excitatory principal cells with a diverse population of inhibitory interneurons. One of the most striking features of the diversity of the interneurons is the specificity of their axonal arborizations. Each class of interneuron targets a specific subcellular compartment; for instance, different populations of interneurons mediate somatic and dendritic inhibition. However, in order to fully appreciate the implications of having different compartments under discrete inhibitory control we must know three things about each class of interneuron: its impact on the postsynaptic cell, the patterns of activity through which it is recruited, and its regulation by neuromodulators. We argue that these three properties will allow us to define the role of an inhibitory interneuron in the circuit. In order to investigate the roles of the diverse population of interneurons, we made intracellular recordings from identified interneurons in slices of the rat hippocampus. Through paired intracellular and extracellular recordings, we found that GABA release from both somatic and dendritic targeting interneurons results in the hyperpolarization of pyramidal cells. Within the groups of somatic and dendritic targeting interneurons there was additional diversity in their intrinsic properties, patterns of excitation, and modulation. By dividing the interneurons according to both the location of their axonal arborization (i.e. somatic or dendritic) and their intrinsic firing patterns (i.e. regular and fast spiking), we were able to define four relatively homogenous populations with distinct patterns of recruitment and impacts on their targets. In addition we found that neuromodulators could independently suppress the different classes of interneurons, suggesting that the network can actively regulate the timing and strength of inhibition. This work provides evidence for the precise roles of somatic and dendritically targeting interneurons in coordinating network activity. In addition, it proposes a methodology for understanding the role of the diverse population of inhibitory interneurons in the intact cortical circuit

Precision pharmacology aims to manipulate specific cellular interactions within complex tissues. In this pursuit, we introduce DART.2 (drug acutely restricted by tethering), a second-generation cell-specific pharmacology technology. The core advance is optimized cellular specificity-up to 3,000-fold in 15 min-enabling the targeted delivery of even epileptogenic drugs without off-target effects. Additionally, we introduce brain-wide dosing methods as an alternative to local cannulation and tracer reagents for brain-wide dose quantification. We describe four pharmaceuticals-two that antagonize excitatory and inhibitory postsynaptic receptors, and two that allosterically potentiate these receptors. Their versatility is showcased across multiple mouse-brain regions, including cerebellum, striatum, visual cortex and retina. Finally, in the ventral tegmental area, we find that blocking inhibitory inputs to dopamine neurons accelerates locomotion, contrasting with previous optogenetic and pharmacological findings. Beyond enabling the bidirectional perturbation of chemical synapses, these reagents offer intersectional precision-between genetically defined postsynaptic cells and neurotransmitter-defined presynaptic partners.