Phenotypic screening with primary neurons to identify drug targets for regeneration and degeneration

•Phenotypic screening identifies targets and probes for complex biological processes.•Phenotypic screening is very successful at identifying first in class pharmaceuticals.•Target based screening can optimize compounds for therapeutics.•Combining phenotypic and target based screening is a power approach.

High-throughput, target-based screening techniques have been utilized extensively for drug discovery in the past several decades. However, the need for more predictive in vitro models of in vivo disease states has generated a shift in strategy towards phenotype-based screens. Phenotype based screens are particularly valuable in studying complex conditions such as CNS injury and degenerative disease, as many factors can contribute to a specific cellular response. In this review, we will discuss different screening frameworks and their relative utility in examining mechanisms of neurodegeneration and axon regrowth, particularly in cell-based in vitro disease models.