Neuropeptides and their receptors in synaptic plasticity and epileptogenesis

A. Vezzani, M. Rizzi, M. Conti, D. Moneta, T. Ravizza, M. Gobbi

Research output: Contribution to journalArticle

Abstract

The presence and distribution within the CNS of various peptides and their receptors, many of which were originally characterized in non-neural tissues, have raised many questions regarding their function and mechanisms of action. Many neuroactive peptides are often co-localized in neurons with classical neurotransmitters (i.e. biogenic amines or amino acids) but differ from them in their biosynthesis, axonal transport, storage and extracellular inactivation, and in the frequencydependence of their release. Thus, peptides are preferentially released from neurons under conditions of elevated neuronal activity (i.e. high frequency stimulation or burst firing), including pathological hyperactivity such as seizures. Recently, somatostatin (SRIF) and neuropeptide Y (NPY) have attracted much attention for their possible involvement in epilepsy. Despite their widespread distribution in the CNS. only brain regions playing a crucial for the initiation and propagation of epileptic discharges, show changes in peptides mRNA expression, their levels and cellular distribution following seizures. In particular, ectopic expression of SRIF and NPY is respectively observed in CA3 pyramidal neurons and in granule cells and their mossy fibres after experimentally-induced seizures suggesting that peptides are released at new synaptic sites in epileptic tissue. SRIF and NPY synthesis is enhanced in hilar interneurons after kindling while these neurons degenerate after status epilepticus. Seizure models also produce changes in peptides release and lasting adaptive modifications in their receptor subtypes. In particular, in both kindling and kainate models, Y 2 receptors are up-regulated on mossy fibres while Y 1 receptors are decreased on granule cell dendrites. Similar changes were found in human epileptic tissue (Günther Sperk, unpublished observations). SRIF receptors (sst2 subtype) are reduced in the outer molecular layer after kindling while sst3 and sst4 subtypes appear to be decreased on CA1/CA3 pyramidal neurons after status epilepticus. In the attempt to shed some light on the functional consequences of these changes, we investigated the effect of preferential or selective ligands to the various peptide receptor subtypes on experimentally-induced seizures in rats. We found that the intracerebral application of sst2 receptor agonists protects rats from acute and chronic seizure susceptibility induced by kainic acid. Inactivation of endogenous SRIF by a specific antibody delays hippocampal kindling rate. Thus, this peptide has both anticonvulsive and antiepileptogenic properties in rodents. Intracerebral injection of selective Y1 receptor antagonists protects against kainate-induced seizures and delays the occurrence of stage 5 seizures in rapidly-kindled rats. Intracerebral application of NPY analogs preferentially acting as agonists at Y 2 receptor subtypes reduces seizure susceptibility to kainate and pentylenetetrazol. Thus, seizures are likely to induce lasting changes in peptidergic neurotransmission. These changes may differentially affect hippocampal excitability and epileptogenesis depending on the receptor subtypes which are preferentially involved. Our pharmacological evidence suggests that peptide receptors may be considered as novel targets for developing new compounds for anticonvulsive treatment.

Original languageEnglish
Pages (from-to)197
Number of pages1
JournalItalian Journal of Neurological Sciences
Volume20
Issue number3
Publication statusPublished - 1999

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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