Roles For

A. Hippocampal Information Processing

This specific role harkens back to the extensive discussion we had in Chapters 4-6 concerning the capacity of LTP to serve as a memory trace that is triggered when certain associative events have occurred. For example, we talked about how back-propagating action potentials coupled with neuromodulatory neurotransmitter receptor activation plus synaptic glutamate could give three-way coincidence detection.

This type of molecular information processing, resulting in a persisting change (LTP) can function to allow temporary storage of information integrated from a wide variety of sensory inputs. A principal example of this may be in learning complex visuo-spatial tasks such as the Morris water maze. These types of mechanisms can also allow the monitoring of the emotional valence of an experience, or assessment of the attentive state of the animal. In broad terms, these mechanisms likely contribute to the role of the hippocampus in making multimodal associations and storing these associations for some period of time.

For illustrative purposes I'll describe a few experiments supporting this idea of a role for NMDA receptor-dependent LTP in these types of information processing.

One relevant paradigm is the formation of pyramidal neuron place fields. It is clear that LTP is not necessary for hippocampal place field formation (30-33). However, molecular disruptions that block LTP formation do have consistent effects on place fields. Specifically, loss of LTP is associated with a decreased stability of place fields (33). There also are effects on the spatial specificity of place fields and the coordinated firing of pyramidal neurons that have the same place fields (30). Overall, these data provide one explanation for the loss of hippocampus-dependent spatial learning in animals deficient in LTP. The effects on place fields specifically are consistent with the idea that NMDA receptor-dependent LTP is necessary in forming an accurate and lasting representation of complex visuo-spatial environments.

NMDA receptor-dependent LTP in area CA1 of the hippocampus also appears to be necessary for multimodal associative learning (34). Mice can learn to form complex associations among three different odor cues in order to make predictions about food rewards. In one type of task, mice must learn that odor A + B is different from odor B + C is different from odor C + A. Mice deficient in NMDA receptor-dependent LTP in area CA1 are deficient in making the types of complex multiple associations necessary to efficiently execute this task (34). Thus, LTP appears to be necessary for the formation of relational memories involving complex associative information processing.

A final and fascinating recent example illustrates that NMDAR-dependent processes are necessary for reconstituting spatial locations using partial visual cues (35). In these experiments, NMDA receptors were selectively eliminated in hippocampal area CA3 using genetic engineering approaches. Mice deficient in NMDA receptor-dependent LTP in area CA3 can learn the Morris water maze normally but exhibit a deficiency in being able to recall the hidden platform location when they are primed for recollection using a partial set of visual cues. In other words, animals are selectively deficient in recalling a spatial location when some of the training-associated visual stimuli are removed. These deficits are associated with a similar derangement of place cell activity in a partial-cue environment. These findings indicate that hippocampal LTP is involved in the animal forming a complete and unified representation of a complex set of visual stimuli.

Two important experiments using infusion of the NMDA receptor antagonist APV into the CNS also bear directly on this idea—in fact, these two papers from Richard Morris's lab are seminal findings that both shaped our general thinking in the area and served as a foundation for much of the later work in this area. In a pioneering study, Richard and his colleagues found that intraventricular infusions of APV, at concentrations that block LTP induction, block spatial learning

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