cortistatin-14 and Seizures

Signaling of brain-derived neurotrophic factor (BDNF) via tropomyosin receptor kinase B (TrkB) plays a critical role in the maturation of cortical inhibition and controls expression of inhibitory interneuron markers, including the neuropeptide cortistatin (CST). CST is expressed exclusively in a subset of cortical and hippocampal GABAergic interneurons, where it has anticonvulsant effects and controls sleep slow-wave activity (SWA). We hypothesized that CST-expressing interneurons play a critical role in regulating excitatory/inhibitory balance, and that BDNF, signaling through TrkB receptors on CST-expressing interneurons, is required for this function. Ablation of CST-expressing cells caused generalized seizures and premature death during early postnatal development, demonstrating a critical role for these cells in providing inhibition. Mice in which TrkB was selectively deleted from CST-expressing interneurons were hyperactive, slept less and developed spontaneous seizures. Frequencies of spontaneous excitatory post-synaptic currents (sEPSCs) on CST-expressing interneurons were attenuated in these mice. These data suggest that BDNF, signaling through TrkB receptors on CST-expressing cells, promotes excitatory drive onto these cells. Loss of excitatory drive onto CST-expressing cells that lack TrkB receptors may contribute to observed hyperexcitability and epileptogenesis.

Topics: Animals; Behavior, Animal; Brain; Brain Waves; Brain-Derived Neurotrophic Factor; Excitatory Postsynaptic Potentials; Hyperkinesis; Interneurons; Locomotion; Membrane Glycoproteins; Mice, Inbred C57BL; Mice, Knockout; Neural Inhibition; Neuropeptides; Protein-Tyrosine Kinases; Seizures; Sleep; Synaptic Transmission

Cortistatin (CST) is a presumptive neuropeptide that shares 11 of its 14 amino acids with somatostatin (SST). CST and SST are expressed in partially overlapping but distinct populations of cortical interneurons. In the hippocampal formation, most CST-positive cells are also positive for SST. In contrast to SST, administration of CST into the rat brain ventricles reduces locomotor activity and specifically enhances slow wave sleep. Intracerebroventricular injection of CST or SST has been shown to protect against the neurotoxic effects of kainic acid. Here, we show that CST and SST mRNAs respond differently to kainate-induced seizures. Furthermore, comparison of the upstream sequences from the CST and SST precursor genes reveal that they contain binding motifs for different transcriptional regulatory factors. Our data demonstrate that CST and SST, which are often co-expressed in the same neurons, are regulated by different stimuli.

Topics: Amino Acid Sequence; Animals; Base Sequence; Binding Sites; Cerebral Cortex; Cloning, Molecular; Excitatory Amino Acid Agonists; Gene Expression Regulation; Genes; Hippocampus; In Situ Hybridization; Interneurons; Kainic Acid; Mice; Molecular Sequence Data; Nerve Tissue Proteins; Neuropeptides; Promoter Regions, Genetic; Protein Precursors; Rats; Rats, Sprague-Dawley; Regulatory Sequences, Nucleic Acid; RNA, Messenger; Seizures; Somatostatin; Transcription Factors; Transcription, Genetic

Cortistatin (CST-14) is a recently discovered endogenous peptide which shares similarity to somatostatin and binds to somatostatin receptors. In this study, we show that CST-14 exhibits anticonvulsive and neuroprotective effects in rats. Injection of rats with kainic acid (KA; 10 mg/kg; i.p.) generated a strong seizure activity which was attenuated by the i.c.v. application of 1 and 10 nmol CST-14 when given 10 min before KA. Moreover, 3 days after KA injection, a marked loss of neurons in cortex and hippocampus of rats was observed which was inhibited by pretreatment with CST-14. An immunohistochemical analysis using specific antibodies revealed that KA reduced immunoactive sst2A and sst3 somatostatin receptors in the hippocampus-an effect which was largely prevented by pretreatment with CST-14. Superfusion of hippocampal slices with CST-14 also reduced the stimulated release of 3H-d-aspartate. We conclude that CST-14 exerts neuroprotective effects by binding to somatostatin receptors which in turn leads to a reduced release of excitotoxic neurotransmitters.

Topics: Animals; Brain; Catheterization; Cell Count; Hippocampus; Immunohistochemistry; Injections, Intraperitoneal; Injections, Intraventricular; Kainic Acid; Male; Neurons; Neuropeptides; Rats; Rats, Wistar; Receptors, Somatostatin; Seizures