Roles in Information Coding

During development, the roles that APs play in the nervous system vary substantially (Figure 3; see below). Interestingly, many neurons fire APs prior to synapse formation. Several lines of evidence indicate that early-appearing APs play a developmental role. After synapse formation, APs take part in mechanisms that select and/or eliminate specific connections. In the mature nervous system, APs contribute to plasticity mechanisms in addition to being essential for the rapid processing of information.

1.13.4.1 Prior to Synapse Formation

Many aspects of neuronal differentiation begin prior to synapse formation. Importantly, many neurons acquire electrical excitability prior to synapse formation, thus allowing neuronal activity to influence subsequent aspects of differentiation (Holliday and Spitzer, 1990). For example, soon after neurons exit the cell cycle and initiate postmitotic differentiation, they often migrate long distances and take up residence at distant sites. Blocking electrical activity can affect migratory patterns of embryonic neurons for both invertebrates and vertebrates

(Komuro and Rakic, 1992; Tam et al., 2000). Neurons differentiate biochemically and often synthesize and secrete neurotransmitter prior to synapse formation. Perturbations of excitability alter biochemical differentiation of neurons, resulting in inappropriate neurotransmitter synthesis (Gu and Spitzer, 1995; Borodinsky et al., 2004). Morphological differentiation also occurs during this period, notably axon outgrowth and initial contact of targets. Blockade of activity also perturbs this important aspect of neuronal differentiation (Cohan and Kater, 1986; Gu et al., 1994). As discussed further below, electrical membrane properties are also developmentally regulated. Patterns of early activity influence acquisition of mature channel properties (Desarmenien and Spitzer, 1991; Gomez and Spitzer, 1999).

A common finding for effects of activity prior to synapse formation concerns its dependence on calcium ions. The majority of studies indicate that calcium ions act as intracellular messengers and participate in mechanisms that translate patterns of activity into developmental programs (for review, see Spitzer et al., 2004). As we discuss below, many neurons fire long-duration calcium-dependent APs prior to synapse formation, thus accounting, at least in part, for the calcium dependence.

1.13.4.2 During Synapse Formation and Early Circuit Activity

Synapses can form in the absence of neural impulses (Verhage et al., 2000; Trachtenberg et al., 2002; De Paola et al., 2003). However, the maintenance of synapses requires transmitter secretion that normally depends upon impulse propagation (for review, see Sanes and Lichtman, 2001). Moreover, in several instances, after synapses initially form,

Young neurons

Action potential

Mature neurons

Adult neurons

Young neurons

Mature neurons

Adult neurons

Action potential

Migration Biochemical differentiation Morphological differentiation lon channel maturation

Synpase elimination/selection Biochemical differentiation Morphological differentiation lon channel maturation

Rapid signaling Flne-tuning of circuits Plasticity Homeostasis

Migration Biochemical differentiation Morphological differentiation lon channel maturation

Synpase elimination/selection Biochemical differentiation Morphological differentiation lon channel maturation

Rapid signaling Flne-tuning of circuits Plasticity Homeostasis

Figure 3 AP roles change during development. In neurons, APs play several roles in addition to rapid processing of information. Prior to synapse formation, APs play developmental roles. During the early stages of synapse formation, APs function in mechanisms that eliminate or stabilize specific connections. In the adult nervous system, APs contribute to plasticity mechanisms.

there is a period of pruning or synapse elimination. For example, at the neuromuscular junction, muscle fibers that receive inputs from multiple axons become singly innervated (for review, see Colman and Lichtman, 1993). Also, in the cerebellum, Purkinje cells are initially innervated by more than one climbing fiber but later respond to inputs from only one (Mariani and Changeux, 1981). Similar observations have been made for developing synapses in the visual, auditory, and autonomic nervous systems (Lichtman, 1977; Shatz and Stryker, 1988).

During development, activity regulates neuronal arbor growth by regulating branch lifetime in retinal ganglion cell axons and tectal dendrites of Xenopus and zebra fish larvae (Rajan and Cline, 1998; Rajan et al., 1999; Lohmann et al., 2002; Schmidt, 2004). Activity-dependent expression of structural proteins may also be involved in synapse stabilization and dendritic branch formation (Ziv and Smith, 1996; Lichtman, 2000; Star et al., 2002; Fukazawa et al., 2003; for review, see Steward and Schuman, 2001; Hua and Smith, 2004). Moreover, activity promotes secretion of neurotrophins that have multiple effects on synaptic development and function as well as ion channels (Nick and Ribera, 2000; for review, see Poo, 2001; Lu and Je, 2003; Figure 4).

1.13.4.3 Mature Nervous System

In the mature nervous system, a principal role of the AP is transduction, conduction, and processing of information (Eggermont, 1998; Sanger, 2003). However, even at these stages, AP generation contributes to mechanisms that alter the nervous system both structurally and functionally. For example, activity sculpts the time course of elimination of Rohon-Beard cells from the spinal cord of larval zebra fish (Svoboda et al., 2001). Neural activity also promotes both short- and long-term synaptic changes and affects the maintenance, synthesis, and release of neurotrophins (Madison et al., 1991; Poo, 2001; Lu and Je, 2003).

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