Characterizing the Site and Mode of Action of Dynorphin at Hippocampal Mossy Fiber Synapses in the Guinea Pig

Abstract

Extracellular field potential recordings from the CA3 region in guinea pig hippocampal slices were used to study the release and action of dynorphin at the mossy fiber synapse. Dynorphin A(1-17) or U69593 inhibited mossy fiber synaptic responses in preparations in which the CA3 region was surgically isolated from the rest of the hippocampus. This inhibition was completely reversed by the 1 selective antagonist nor-BNI, thus establishing the presence of functional 1 receptors in CA3. Inhibitory effects of dynorphin on mossy fiber responses were unaltered in the presence of the N-or P-type Ca 2ϩ channel blockers, -CgTx or -Aga IVA, respectively. This indicates that the action of dynorphin is independent of the particular type of Ca 2ϩ channel that mediates transmitter release at the mossy fiber terminal. Heterosynaptic inhibition of mossy fiber responses was observed in the presence of nifedipine, -CgTx, or -Aga IVA, indicating that dynorphin release does not depend specifically on L-, N-, or P-type Ca 2ϩ channels. The blockade of heterosynaptic inhibition by the membranepermeant Ca 2ϩ chelator EGTA-AM suggests the involvement of a slow Ca 2ϩ -dependent process in dynorphin release. On the basis of a variety of experimental evidence, we propose that the time course of heterosynaptic inhibition is determined primarily by the time course of clearance of dynorphin in the extracellular space.

Differential Target-Dependent Actions of Coexpressed Inhibitory Dynorphin and Excitatory Hypocretin/Orexin Neuropeptides

“…After washout, the membrane potential returned to the control level. Dynorphin actions are mediated primarily by the receptor in other brain regions (Castillo et al, 1996;Ogura and Kita, 2000;Shuster et al, 2000). When hypocretin neuron cells were pretreated with the receptor antagonist, nor-BNI (1 M), dynorphinhyperpolarizing actions were blocked (n ϭ 7; p Ͼ 0.05) (Fig.…”

Retrograde Opioid Signaling Regulates Glutamatergic Transmission in the Hypothalamus

“…Many of these studies have implicated an opioid-mediated inhibition of presynaptic Ca 2ϩ channels (Rusin et al, 1997;Hjelmstad and Fields, 2003) or the activation of presynaptic K ϩ channels (Simmons and Chavkin, 1996;Vaughan et al, 1997). Other studies, however, rule out Ca 2ϩ channels and/or K ϩ channels (Castillo et al, 1996;Ford et al, 2007), indicating that the nature of a unifying mechanism remains unresolved. Our data provide evidence for a novel form of inhibition, whereby neither of these mechanisms contribute to the decrease in glutamate release after activation of -opioid receptors.…”

“…These retrograde signals are chemically diverse, are recruited under different conditions, and have distinct effects on the presynaptic terminal (Ludwig and Pittman, 2003). The opioid peptide, dynorphin, powerfully inhibits excitatory transmission in the nervous system (Weisskopf et al, 1993;Castillo et al, 1996;Simmons and Chavkin, 1996;Hjelmstad and Fields, 2003;Honda et al, 2004;Ford et al, 2007). In stark contrast to the wealth of data implicating a role for exogenous dynorphin in modulating synaptic transmission, there are only a few examples, and only in the hippocampus, of dynorphin acting as a retrograde messenger (Wagner et al, 1993).…”

Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity

“…Slow buffers such as EGTA affect transmitter release after an unconditioned stimulus only if release sites are not in direct vicinity to the site of Ca 2ϩ influx, the voltage-dependent Ca 2ϩ channels (8). In some preparations [squid giant synapse (27) and pyramidal-pyramidal synapses (31)], where influx and release are apparently tightly coupled together, EGTA does not inhibit markedly the probability of release, whereas in other preparations [crayfish neuromuscular junction (32) or hippocampal mossy fiber synapse (33,34)], where the coupling is looser, a significant reduction is observed. Our finding that the probability of failures is not different in PVϩ͞ϩ and in PVϪ͞Ϫ strains, and that it is not modified by addition of EGTA in PVϪ͞Ϫ mice ( Table 1), suggests that the interneuron-Purkinje cell synapse falls in the first category, where release sites are closely associated to voltage-dependent Ca 2ϩ channels.…”