Can in vitro assessment provide relevant end points for cognitive drug programs?

Several start-up biotechnology companies have been created with the primary intent of developing cognitive enhancers. In addition, established pharmaceutical companies also frequently focus their efforts on cognitive drug discovery. In many instances, the rationale and evidence for these endeavors are based largely on in vitro assessments. In particular, the experimental paradigm, know as long-term potentiation (LTP), a cellular model of synaptic plasticity and memory encoding, is being increasing used preclinically for assessing potential nootropic drugs in vitro. Central to this thinking is the idea that the modulation of LTP and/or glutamate receptors are the key criteria that must be met for the development of cognitive enhancers. However, programs targeting the NMDA receptor, a glutamate receptor subtype, over the years have been less than fruitful. In addition, skeptics criticize the relevance of some in vitro tests such as LTP for simulating human cognitive function. Given these considerations, one may wonder if in vitro assessments in general, and the LTP paradigm in particular, provide relevant end points for cognitive drug discovery and development programs. The focus of this article is to address this question and to present evidence as to why in vitro assessment is still critical to the success of any cognitive drug program.