Figure 5 Patterns of AP development. Three patterns have been described. In the first, APs are of long duration when first present, but mature in time to the more stereotypic brief spikes, characteristic of mature neurons. The second pattern consists of APs that show little developmental regulation and are brief and sodium-dependent from the time of first appearance. The third pattern, characteristic of some sensory neurons, consists of APs at early stages followed by the loss of AP generation. At adult stages, neurons of the class 3 pattern respond with graded depolarization or hyperpolarizations to sensory stimuli.
Spitzer, 1991; Ribera and Spitzer, 1992; Spitzer et al., 2000). We discuss these two patterns in more detail below.
The third developmental pattern consists of an early period of electrical activity followed by loss of AP generation. This pattern appears to be unique to sensory cells and consists of an early transient period of excitability followed by the generation of graded potentials in response to sensory stimuli (Beutner and Moser, 2001). Interestingly, the available evidence implicates the transiently appearing APs in proper development of sensory neurons (Beutner and Moser, 2001; Brandt et al., 2003).
The class 1 pattern of AP development consists of APs that are initially of long duration (5-500 ms; Spitzer and Lamborghini, 1976; Baccaglini and Spitzer, 1977). The early-appearing APs can be generated in the absence of extracellular sodium or in the presence of the sodium channel blocker tetrodo-toxin and are eliminated by substitution of calcium in the extracellular media. Hence, these APs are described as calcium-dependent. In this respect, the class 1 pattern is similar to the third pattern mentioned above: the early APs that are transiently expressed by sensory neurons are calcium-dependent (Beutner and Moser, 2001).
As development proceeds, the AP duration becomes progressively briefer. In addition, the AP acquires sensitivity to blockers of voltage-gated sodium channels (e.g., tetrodotoxin) and insensitiv-ity to calcium channel blockers (e.g., cobalt). The later-appearing APs are hence considered to be sodium-dependent. Examples of excitable cells displaying the class 1 pattern of development include amphibian primary spinal neurons, neurons of the rat dorsal nucleus of the vagus, chick motor neurons, ferret lateral geniculate neurons, and rat nucleus accumbens neurons (Spitzer, 1976; Spitzer and Lamborghini, 1976; Baccaglini and Spitzer, 1977; McCobb et al., 1990; Ramoa and McCormick, 1994; Belleau and Warren, 2000; for review, see Spitzer, 1991; Moody, 1995).
The class 2 pattern of AP development consists of APs that have brief durations from the time of their first appearance. The APs initially expressed are and remain sodium-dependent as differentiation proceeds. Further, the AP duration does not change significantly. Examples of cells displaying the class 2 pattern include chick ciliary ganglion neurons, quail mesencephalic neural crest cells, rat spinal and phrenic neurons, grasshopper interneurons, and amphibian myocytes (Goodman and Spitzer, 1981; Bader et al., 1983, 1985; DeCino and Kidokoro, 1985; Henderson and Spitzer, 1986; Krieger and Sears, 1988; Ziskind-Conhaim, 1988a, 1988b).
Even though several different types of ion channel underlie AP generation, the principal difference between the three patterns of AP development concerns developmental regulation of potassium current (Barish, 1986; Krieger and Sears, 1988; O'Dowd et al., 1988; McCobb et al., 1989; Nerbonne and Gurney, 1989; Ribera and Spitzer, 1989,1990). The class 1 pattern reflects a program of ion channel regulation in which voltage-gated potassium channels are present at low density and have slow activation properties when APs are initially expressed and of long duration. The subsequent developmental shortening of the AP duration is due to a progressive increase in potassium channel density with concomitant changes in channel activation properties (Barish, 1986; O'Dowd et al., 1988; Ribera and Spitzer, 1989; Lockery and Spitzer, 1992; Harris et al., 1998).
Computer reconstructions of the APs recorded from Xenopus spinal neurons support the view that the delayed rectifier potassium current plays the predominant role during AP maturation in amphibian spinal neurons (Barish, 1986; Lockery and Spitzer, 1992).
Regardless of the developmental pattern, calcium and sodium currents appear early in neuronal differentiation (O'Dowd et al., 1988; Alzheimer et al., 1993; Albrieux et al., 2004). Once present, calcium currents may increase in density but often remain stable (Barish, 1986; Gottmann et al., 1988; McCobb et al., 1989). In contrast, sodium currents typically increase in density and undergo kinetic changes (Huguenard et al., 1988; O'Dowd et al., 1988; McCobb et al., 1990; Alzheimer et al., 1993; Pineda et al., 2005).
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