In one sense, the hippocampal slice is a denervated preparation. In the intact animal, the hippocampus receives numerous input fibers that provide modulatory inputs of the neurotransmitters dopamine (DA), norepi-nephrine (NE), serotonin (5HT), and acetylcholine (ACh). Functionally these inputs are largely lost as a necessity of physically preparing the hippocampal slice for the experiment. However, these lost modulatory inputs can be partially reconstituted by directly applying the neuro-transmitters (or more commonly pharma-cologic substitutes) to the slice preparation in vitro. This approach has been used quite successfully to gain insights into the physiologic mechanisms and functional roles of these inputs in the intact brain.
NE-, DA-, and ACh-mimicking compounds can all modulate the induction of LTP at Schaffer-collateral synapses. Specifically, agents acting at various subtypes of receptors for these compounds can increase the likelihood of LTP happening and the magnitude of LTP that is induced. Several examples of this type of modulation experiment are shown in the figure. In one example, 5-Hz stimulation of Schaffer-collateral synapses, for 3 minutes, gives essentially no potentiation. Coappli-cation of isoproterenol, a beta-adrenergic receptor agonist that mimics endogenous NE, converts a nonpotentiating signal into a potentiating one (33). Under other conditions beta-adrenergic agonists can augment the magnitude of LTP induced as well, if different physiologic stimulation protocols are used that evoke modest LTP. Similar types of effects can be observed for activation of various subtypes of receptors for ACh and DA (see reference 15). The basis for this modulation is complex, and we will discuss some of the many sites at which these agents might act in the next chapter.
One known site of action of neuromodu-lators is regulation of back-propagating action potentials in pyramidal neuron den-drites. All these agents, which modulate LTP induction, can modulate the magnitude of back-propagating action potentials (see Panel B). The augmentation of back-propagating action potentials is a means by which these neurotransmitters can enhance membrane depolarization and thereby enhance NMDA receptor opening. We will discuss how this happens at the molecular level in the next chapter.
The growth factor BDNF (brain-derived neurotrophic factor) can also modulate the induction of LTP by a number of mechanisms, at least one of which is presynaptic (see references 34, 35, and 36 and Panel C). BDNF, acting through its cell-surface receptor TrkB, acts on presynaptic terminals to facilitate neurotransmitter release selectively during high-frequency stimulation. This is an interesting example of modulation of LTP induction that is activity-dependent but localized to the presynaptic compartment. The mechanisms controlling the levels of BDNF in the adult hippocampus are not entirely clear at this point, but it is fairly well established that hippocampal BDNF levels can be regulated by a variety of neuronal activity-dependent processes and indeed in response to environmental signals impinging upon the behaving animal.
Overall LTP induction is subject to modulation by a wide variety of extracellular signals. We will return to mechanisms for these processes, and some of their implications for memory formation in the animal, in later chapters.
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