A neuroprotective role for polyamines in a Xenopus tadpole model of epilepsy

Abstract

Polyamines are endogenous molecules involved in cell damage following neurological insults, although it is unclear whether polyamines reduce or exacerbate this damage. We used a developmental seizure model in which we exposed Xenopus laevis tadpoles to pentylenetetrazole (PTZ), a known convulsant. We found that, after an initial PTZ exposure, seizure onset times were delayed in response to a second PTZ exposure 4 h later. This protective effect was a result of activity-dependent increases in synthesis of putrescine, the simplest polyamine. Unlike more complex polyamines that directly modulate ion channels, putrescine exerted its effect by altering the balance of excitation to inhibition. Tectal neuron recordings, 4 h after the initial seizure, revealed an elevated frequency of GABAergic spontaneous inhibitory postsynaptic currents. Our data suggest that this effect is mediated by an atypical pathway that converts putrescine into GABA, which then activates presynaptic GABA(B) receptors. Our data suggest that polyamines have a previously unknown neuroprotective role in the developing brain.

Modeling human neurodevelopmental disorders in theXenopustadpole: from mechanisms to therapeutic targets

“…In a recent study by Bell et al (Bell et al, 2011) involving a protocol consisting of two consecutive PTZ-induced seizures and a combination of behavioral, electrophysiological and pharmacological experiments, it was shown that the first initial PTZ-induced seizure in a tadpole increases the production of polyamines [an observation that had also been reported in a rodent seizure model (Hayashi et al, 1993)]. Elevated polyamine levels were found to boost the production and release of the inhibitory transmitter GABA, which rendered tadpoles less prone to future seizures.…”

“…A protocol to reliably induce controlled seizures in the Xenopus tadpole has been developed (Hewapathirane et al, 2008) and has already led to a fundamental insight into how endogenous polyamines can play a neuroprotective role in response to an epileptic seizure (Bell et al, 2011). …”

“…(5) At the synaptic level, electrophysiology offers a way to quantify maturation of synaptic and intrinsic properties of the cell through recordings of (a) evoked synaptic responses, (b) spiking in response to current injections and (c) spontaneous synaptic activity. The figure is inspired by experimental data published in the following papers: (Aizenman et al, 2002; Bestman et al, 2006; Ruthazer et al, 2006; Pratt and Aizenman, 2007; Hewapathirane et al, 2008; Bollmann and Engert, 2009; Hiramoto and Cline, 2009; Straka, 2010; Bell et al, 2011; Marshak et al, 2012; Miraucourt et al, 2012). …”

Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons

“…GABA production through this alternative evolutionarily conserved pathway also exists in Xenopus tadpole (15) and mammalian cells (16–19). Glial cells can also utilize putrescine to produce GABA during retinal early development (18, 20).…”

Tritiation and characterization of several polyamine natural products

“…It is produced naturally by the decarboxylation of ornithine and serves as a biosynthetic precursor to both spermine and spermidine. Even after decades of intense research, new biological functions continue to be routinely discovered for putrescine (Bell et al, 2011).…”