Serotonin Induces Memory-Like, Rapamycin-Sensitive Hyperexcitability in Sensory Axons ofAplysiaThat Contributes to Injury Responses

Abstract

The induction of long-term facilitation (LTF) of synapses of Aplysia sensory neurons (SNs) by serotonin (5-HT) has provided an important mechanistic model of memory, but little is known about other long-term effects of 5-HT on sensory properties. Here we show that crushing peripheral nerves results in long-term hyperexcitability (LTH) of the axons of these nociceptive SNs that requires 5-HT activity in the injured nerve. Serotonin application to a nerve segment induces local axonal (but not somal) LTH that is inhibited by 5-HT-receptor antagonists. Blockade of crush-induced axonal LTH by an antagonist, methiothepin, provides evidence for mediation of this injury response by 5-HT. This is the first demonstration in any axon of neuromodulator-induced LTH, a phenomenon potentially important for long-lasting pain. Methiothepin does not reduce axonal LTH induced by local depolarization, so 5-HT is not required for all forms of axonal LTH. Serotonin-induced axonal LTH is expressed as reduced spike threshold and increased repetitive firing, whereas depolarization-induced LTH involves only reduced threshold. Like crush- and depolarization-induced LTH, 5-HT-induced LTH is blocked by inhibiting protein synthesis. Blockade by rapamycin, which also blocks synaptic LTF, is interesting because the eukaryotic protein kinase that is the target of rapamycin (TOR) has a conserved role in promoting growth by stimulating translation of proteins required for translation. Rapamycin sensitivity suggests that localized increases in translation of proteins that promote axonal conduction and excitability at sites of nerve injury may be regulated by the same signals that increase translation of proteins that promote neuronal growth.

Characterization of the rapid transcriptional response to long-term sensitization training in Aplysia californica

“…This is consistent with the large body of work showing overlap in the mechanisms of long-term sensitization and hyperalgesia (e.g. Walters, 1987; Weragoda & Walters, 2007). We are now testing if pharmacological inhibition of GlyT2 can block the induction or maintenance of long-term sensitization memory.…”

Molluscan Memory of Injury: Evolutionary Insights into Chronic Pain and Neurological Disorders

“…Some of the general initiating signals that are common to molluscan and mammalian nociceptors, and to neurons displaying long-term plasticity in central neurons of diverse animals are shown in figure 3 . Initiating events for long-term alterations include intense depolarization and Ca 2+ entry consequent to membrane injury or binding of excitatory amino acids, and activation of cell signaling pathways by binding of neuromodulators and growth factors released by neurons [Jankowsky and Patterson, 1999;Kandel, 2001;Weragoda and Walters, 2007] and other cell types [e.g., glia, support cells, and inflammatory cells; Bradley and Finkbeiner, 2002;Gibbs et al, 2008]. Changes in gene expression are triggered by Ca 2+ entry accompanying action potentials propagating into the soma [Saha and Dudek, 2008], as well as retrograde signals transported to the nucleus from sites of axonal injury [Gunstream et al, 1995;Lin et al, 2003; or intense synaptic stimulation [Otis et al, 2006;Lai et al, 2008].…”

Toward locating the source of serotonergic axons in the tail nerve of Aplysia

“…Further experiments would need to be conducted in Aplysia to determine whether this was the case for the axons in p9. The potential of 5-HT release in the nerve is significant because 5-HT has been implicated as mediating responses to injury in the nerve (Weragoda and Walters 2007). 5-HT might be taken up in the periphery, transported along the axon to be released at varicosities in the nerve.…”

“…Previous work showed that electrical stimulation of the tail or just the tail nerve, pedal nerve 9 (p9), causes sensitization of the tail withdrawal reflex (Philips et al 2011), the release of 5-HT (Marinesco and Carew 2002), and evokes cellular analogs of behavioral sensitization (Walters et al 1983). Crushing sensory axons in p9 causes long-term hyperexcitability of the axons, which resembles the effects of sensitization and requires 5-HT (Weragoda and Walters 2007). Despite the importance of 5-HT to these studies, the neurons that release 5-HT in response to stimulation or injury of p9 have not been identified.…”