Hippocampal LTP and memory in mouse strains: is there evidence for a causal relationship?

The mechanisms underlying memory are under intense investigation. One of the most promising candidates at the cellular level is long-term potentiation (LTP). Numerous pharmacological and molecular genetic manipulations have led to alteration in both LTP and memory. However, the causal relationship between these phenotypical changes is debated. The problem of causality can be addressed in numerous ways. One suggestion is to investigate natural variation in both LTP and memory performance in mouse strains. If variation in synaptic and behavioral phenomena is found, correlation between these traits may be investigated. The advantages and disadvantages of this approach are discussed. An empirical example using four mouse strains is also presented to highlight some general problems. The following arguments are made. First, multiple electrophysiological and behavioral paradigms with idiosyncratic condition characteristics should be conducted to avoid false-positive findings due to alterations unrelated to memory and its mechanisms. Multiple stimulation and memory protocols may also allow one to study the complexity and multiplicity of processes. Second, analysis of a large number of mouse strains may be needed to avoid false interpretation of results due to spurious gene associations and/or linkage disequilibrium. Third, quantitative genetic analysis using, for example, diallele crosses, may be employed to properly investigate biologically meaningful, i.e., genetic, effects. It is concluded that with the use of additional methods (e.g., QTL analysis, gene expression arrays, and biochemical analysis) providing converging evidence, analysis of mouse strains will be instrumental in addressing the question regarding the role LTP may play in memory.