Molecular Tools for Targeted Control of Nerve Cell Electrical Activity. Part II

Abstract

In modern life sciences, the issue of a specific, exogenously directed manipulation of a cells biochemistry is a highly topical one. In the case of electrically excitable cells, the aim of the manipulation is to control the cells electrical activity, with the result being either excitation with subsequent generation of an action potential or inhibition and suppression of the excitatory currents. The techniques of electrical activity stimulation are of particular significance in tackling the most challenging basic problem: figuring out how the nervous system of higher multicellular organisms functions. At this juncture, when neuroscience is gradually abandoning the reductionist approach in favor of the direct investigation of complex neuronal systems, minimally invasive methods for brain tissue stimulation are becoming the basic element in the toolbox of those involved in the field. In this review, we describe three approaches that are based on the delivery of exogenous, genetically encoded molecules sensitive to external stimuli into the nervous tissue. These approaches include optogenetics (overviewed in Part I), as well as chemogenetics and thermogenetics (described here, in Part II), which is significantly different not only in the nature of the stimuli and structure of the appropriate effector proteins, but also in the details of experimental applications. The latter circumstance is an indication that these are rather complementary than competing techniques.

Connectivity of the Brain in the Light of Chemogenetic Modulation of Neuronal Activity

“…DREADD is the most popular chemogenetic approach used to study the regulation of various aspects of brain activity by neuronal networks in experimental animals [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. In addition to solving fundamental science tasks, chemogenetics can potentially become useful for restructuring the pathological mechanisms of nervous and mental diseases and regulate them using designer drugs [ 29 ].…”

“…Chemogenetic inhibition/inactivation in experimental neurobehavioral neuroscience is often referred to as chemogenetic silencing. DREADDs enter the brain either as part of a transgene, whose expression in the structure of interest is achieved by crossing specific mouse lines [ 31 ], or as part of a vector, which is usually based on an adeno-associated virus [ 24 , 25 , 26 , 27 , 28 ]. Stereotaxic administration of the viral vector provides its localization in the brain structure of interest, while the promoter governing the expression ensures the presence of the DREADD in the desired type (or types) of cells.…”

The DREADDful Hurdles and Opportunities of the Chronic Chemogenetic Toolbox

“…Although DREADDs form the leading chemogenetic platform, other approaches were also developed [ 6 , 7 , 31 ], such as the pharmacologically selective actuator/effector module (PSAM/PSEM) tool. This platform is not based on GPCR signaling, but instead hijacks ligand-gated ion channels [ 6 , 7 , 32 ].…”

“…Although DREADDs form the leading chemogenetic platform, other approaches were also developed [ 6 , 7 , 31 ], such as the pharmacologically selective actuator/effector module (PSAM/PSEM) tool. This platform is not based on GPCR signaling, but instead hijacks ligand-gated ion channels [ 6 , 7 , 32 ]. Due to the ionotropic mechanism of action, the PSAM/PSEM platform leans more towards optogenetics, also in terms of the timescale of neuromodulation, i.e., ±30 min of neuronal activation upon stimulation [ 32 , 33 ].…”

“…On the other hand, hM4Di inhibits the adenylyl cyclase cascade and activates inward rectifying potassium channels, leading to membrane hyperpolarization [ 2 , 4 , 5 ]. Yet, many other DREADD receptors exist, such as hM3Ds and rM3D; or KORDi, which is activated by salvinorin B instead of CNO [ 6 , 7 ].…”