The Hippocampus Is Required for Memory Formation
Studies in Aplysia and in other model organisms, including Drosophila melanogaster and mice, have begun to reveal many of the molecular mechanisms underlying experience-dependent synaptic plasticity. Clinical studies in humans as well as experimental studies in animals have shown that the hippocampus is required for the formation of long-term memories. Humans and animals with lesions in their hippocampus can form short-term memories and maintain their old memories, but are no longer able to form new long-term memories. Not only is the hippocampus critical for long-term memory formation, but its anatomy also makes it especially suitable for electrophysiological studies of synaptic connectivity. As shown in Figure 22-42, the hippocampus consists of three sequential pathways (perforant, mossy fiber, and Schaffer collateral pathways), each with discrete cell body layers and axonal and dendritic projections. High-frequency stimulation of the axons of presynaptic neurons in each of these pathways produces a long-lasting strengthening of the connections onto the postsynaptic neurons, called long-term potentiation (LTP), while low-frequency stimulation produces a long-lasting weakening of the connections, called long-term depression (LTD).
FIGURE 22-42 Synaptic plasticity in the mouse hippocampus: long-term potentiation (LTP) and long-term depression (LTD). (a) The mouse hippocampus can be dissected from mouse brain cut into transverse slices, preserving the three sequential synaptic pathways. In the perforant pathway, axons from the entorhinal cortex project to form synapses on dendrites of dentate granule cells (green circles); in the mossy fiber pathway, dentate granule axons synapse on CA3 pyramidal neuron (red triangles) dendrites; and in the Schaffer collateral pathway, CA3 axons synapse on CA1 pyramidal neuron (red triangles) dendrites. The dentate granule cells (green) and the CA3 and CA1 pyramidal cell bodies (red) form discrete somatic layers projecting axons and dendrites into defined pathways. Electrodes can be used to stimulate axonal afferents and record from postsynaptic follower cells, as illustrated for the Schaffer collateral (CA3-CA1) pathway. (b) Trains of low-frequency stimulation or high-frequency stimulation to the axonal fibers produce sustained decreases or increases in synaptic strength, which are measured as the postsynaptic response to a test stimulus. These forms of plasticity are known as long-term depression (LTD) and long-term potentiation (LTP). See V. M. Ho, J. A. Lee, and K. C. Martin, 2011, Science 334:623–628.
While a multitude of studies have shown correlations between LTP, LTD, and memory, in 2013, optogenetic studies succeeded in demonstrating a causal role for synaptic plasticity in producing memories. To do this, the investigators expressed channelrhodopsin in hippocampal neurons in mice and stimulated the neurons with light to induce LTP. Induction of LTP caused the mice to acquire a false memory in which they demonstrated fear to an environment even though they had never encountered a frightening stimulus in that environment!