Pre- and postsynaptic N-methyl-D-aspartate receptors are required for sequential printing of fear memory engrams.

The organization of fear memory involves the participation of multiple brain regions. However, it is largely unknown how fear memory is formed, which circuit pathways are used for "printing" memory engrams across brain regions, and the role of identified brain circuits in memory retrieval. With advanced genetic methods, we combinatorially blocked presynaptic output and manipulated N-methyl-D-aspartate receptor (NMDAR) in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) before and after cued fear conditioning. Further, we tagged fear-activated neurons during associative learning for optogenetic memory recall. We found that presynaptic mPFC and postsynaptic BLA NMDARs are required for fear memory formation, but not expression. Our results provide strong evidence that NMDAR-dependent synaptic plasticity drives multi-trace systems consolidation for the sequential printing of fear memory engrams from BLA to mPFC and, subsequently, to the other regions, for flexible memory retrieval.

Transsynaptic Long-Term Potentiation in the Hippocampus of Behaving Mice.

Long-term potentiation (LTP) is an experimental procedure that shares certain mechanisms with neuronal learning and memory processes and represents a well-known example of synaptic plasticity. LTP consists of an increase of the synaptic response to a control stimulus following the presentation of a high-frequency stimulation (HFS) train to an afferent pathway. This technique is studied mostly in the hippocampus due to the latter's high susceptibility and its laminar nature which facilitates the location of defined synapses. Although most preceding studies have been performed in vitro, we have developed an experimental approach to carry out these experiments in alert behaving animals. The main goal of this study was to confirm the existence of synaptic changes in strength in synapses that are post-synaptic to the one presented with the HFS. We recorded field excitatory post-synaptic potentials (fEPSPs) evoked in five hippocampal synapses, from both hemispheres, of adult male mice. HFS was presented to the perforant pathway (PP). We characterized input/output curves, paired-pulse stimulation, and LTP of these synapses. We also performed depth-profile recordings to determine differences in fEPSP latencies. Collected data indicate that the five selected synapses have similar basic electrophysiological properties, a fact that enables an easier comparison of LTP characteristics. Importantly, we observed the presence of significant LTP in the contralateral CA1 (cCA1) area following the control stimulation of non-HFS-activated pathways. These results indicate that LTP appears as a physiological process present in synapses located far away from the HFS-stimulated afferent pathway.