Peptide Cotransmitters as Dynamic, Intrinsic Modulators of Network Activity

Abstract

Neurons can contain both neuropeptides and "classic" small molecule transmitters. Much progress has been made in studies designed to determine the functional significance of this arrangement in experiments conducted in invertebrates and in the vertebrate autonomic nervous system. In this review article, we describe some of this research. In particular, we review early studies that related peptide release to physiological firing patterns of neurons. Additionally, we discuss more recent experiments informed by this early work that have sought to determine the functional significance of peptide cotransmission in the situation where peptides are released from neurons that are part of (i.e., are intrinsic to) a behavior generating circuit in the CNS. In this situation, peptide release will presumably be tightly coupled to the manner in which a network is activated. For example, data obtained in early studies suggest that peptide release will be potentiated when behavior is executed rapidly and intervals between periods of neural activity are relatively short. Further, early studies demonstrated that when neural activity is maintained, there are progressive changes (e.g., increases) in the amount of peptide that is released (even in the absence of a change in neural activity). This suggests that intrinsic peptidergic modulators in the CNS are likely to exert effects that are manifested dynamically in an activity-dependent manner. This type of modulation is likely to differ markedly from the modulation that occurs when a peptide hormone is present at a relatively fixed concentration in the blood.

Keywords: autonomic nervous system; cotransmitter; invertebrate; neuromodulation; neuropeptide.

Figure 1

Peptide release in Aplysia neuromuscular preparations. (A) Effect of firing frequency on peptide release. Release was measured at three different firing frequencies in experiments in which the burst duration and interburst interval were kept constant. Plotted are results corrected to give the release per action potential. Note that there is more release when firing frequency increases (results are replots of data from Vilim et al. (1996a); error bars were omitted for clarity). (B) Effect of interburst interval on peptide release. Release was measured at three different interburst intervals in experiments in which the burst duration and firing frequency were kept constant. Plotted are results corrected to give the release per action potential. Note that increases in interburst interval decrease peptide release (results are replots of data from Vilim et al. (1996a); error bars were omitted for clarity). (C) Peptide release in response to intracellular stimulation of an accessory radula closer (ARC) motor neuron (i.e., stimulation at 12 Hz for 3.5 s every 7 s). The bar indicates the period of neural stimulation. Samples of muscle perfusate were collected every 2.5 min and peptide content was determined using a radioimmunoassay (RIA). Peptide release is expressed as percentage of total release in each experiment. Note that peptide release facilitated greatly and then declined until stimulation ceased (results are replots of data from Karhunen et al. (2001); error bars were omitted for clarity).

Figure 2

Repetition priming is observed when cycles of activity are triggered with an inter-burst interval of 30 s as is indicated in the schematic at the top of the figure. The first cycle that is induced is referred to as having intermediate characteristics. Motor neurons fire at low frequencies and radula opener and closer motor neurons are coactive (as is schematically illustrated in the bottom two rows on the left). With repeated motor program induction, activity becomes ingestive. Radula opener motor neurons are more active during the radula protraction phase of the motor program, and radula closer motor neurons are primarily active during radula retraction (as is schematically illustrated in the bottom two rows on the right).