Long-term potentiation has properties that have long been considered

necessary for the encoding and retrieval of information. Hebbian forms of

LTP exhibit associativity, which appears to be a desirable property, and all
forms of LTP appear to be well suited to rapid learning. One of the more
important challenges entails linking LTP (and LTD, see later) to learning
and memory. This task has proven rather difficult to achieve, although
evidence is accumulating for a causal link between LTP and memory. For
example, learning in rats was verified to induce hippocampal LTP
(Whitlock, Heynen, Shuler, & Bear, 2006). Also, inhibition of PKMζ in the
hippocampus in vivo was demonstrated to disrupt LTP maintenance and
eliminate spatial learning. Instrumental and classically conditioned long-
term memories are similarly erased by locally inhibiting PKMζ in different
brain regions of rats and mice, from days to even weeks and months after
training (Saktor, 2011; Serrano et al., 2008). These results have greatly
strengthened the link between LTP and learning. However, inhibiting PKMζ
does not erase all forms of memory (Serrano et al., 2008).
Additional promising work in this area has come from studies of
genetically engineered knockout mice. The first generation of knockouts
prevented the expression of some factor that was thought to be necessary
for LTP, such as CaM kinase II. Although these studies were intriguing,
they suffered from the fact that the consequences of a gene knockout might
alter brain development and might not be confined to a specific part of the
brain under study. Some of these problems have been overcome in a second
generation of knockouts that have temporal as well as spatial specificity.
For example, temporal and spatial control of gene expression can now be
achieved using binary transgene systems such as tetracycline transactivating
systems and Cre/LoxP recombination systems. The NMDAR gene in only
CA1 pyramidal cells of the hippocampus has been knocked out using the
Cre/LoxP system (Tsien, Huerta, & Tonegawa, 1996). The results provide
strong evidence in favor of the notion that NMDA receptor-dependent
synaptic plasticity at CA3–CA1 synapses is required for the acquisition of
spatial memory. Further spatial specificity can be obtained by using
promoters that are specific for subfields of the hippocampus. For example,
one of the kainate receptor subunits, KA-1, exhibits high levels of
expression in the CA3 pyramidal cell layer. Using the KA-1 promoter and
the α-CaM kinase II promoter, Nakashiba, Young, McHugh, Buhl, and