PSAMs

PSAMs, short for pharmacologically selective actuator modules, are engineered ligand-gated ion channels used in chemogenetics to control neuronal activity. They are activated by synthetic ligands known as pharmacologically selective effector molecules (PSEMs). By combining a ligand-binding domain with an ion channel pore, PSAMs translate the presence of a specific chemical cue into changes in membrane potential.

Design and function

PSAMs are typically designed as chimeric receptors that open or close ion channels when a corresponding PSEM binds. Depending on the channel component, PSAMs can produce excitatory effects (depolarization via cation conductance) or inhibitory effects (hyperpolarization via chloride conductance or other mechanisms). The system enables targeted, reversible modulation of selected neurons or circuits in living animals.

Delivery and targeting

Genes encoding PSAMs are delivered to specific cell populations using viral vectors and cell-type–specific promoters or other targeting strategies. Once expressed, neurons carrying PSAMs respond to systemically administered or locally applied PSEMs, which are designed to be pharmacologically inert at native receptors and to cross biological barriers as needed. This arrangement aims to provide precise temporal control over neural activity with relatively straightforward experimental manipulation.

Applications and limitations

PSAM/PSEM technology is used to study the causal roles of defined neural circuits in behavior, perception, and physiology. Its strengths include reversible and relatively rapid control with cell-type specificity. Limitations include potential off-target pharmacology, variability in expression levels, pharmacokinetic constraints of the ligands, and the need for careful controls to separate effects of the actuator from the system being studied.

Relation to other technologies

PSAMs are part of the broader chemogenetic family, alongside DREADDs, and are often considered complementary to optogenetics. They offer different speed, control, and logistical trade-offs that can suit particular experimental goals.