Neuropeptide systems in temporal lobe epilepsy

Neuropeptides commonly function as co-transmitters alongside classical neurotransmitters within the same neuron. In temporal lobe epilepsy (TLE), the expression of numerous neuropeptides in the brain is profoundly altered. These changes may reflect activity-dependent regulation of the respective neuronal populations-often associated with enhanced neuronal firing and co-release of neuropeptides with classical transmitters-but may also exert direct functional effects through activation of peptide-specific receptors. This review summarizes alterations in neuropeptide systems in experimental models of TLE and evaluates their functional relevance for epileptogenesis and seizure modulation. Notably, neuropeptide expression patterns in rodent models are not uniformly recapitulated in human TLE. For example, Y2 receptors are markedly upregulated in excitatory mossy fibers of the rat hippocampus, whereas in human TLE they are predominantly overexpressed in interneurons. Similarly, dynorphin expression is typically downregulated in granule cell mossy fibers in most animal models, yet strongly upregulated in the same neuronal population in patients with TLE. Dynorphin transcription is regulated by a promoter region containing a polymorphism associated with reduced seizure susceptibility in humans. Among neuropeptide systems, neuropeptide Y (via Y2 and Y5 receptors), dynorphin (via κ-opioid receptors), galanin (via GAL1 and GAL2 receptors), and somatostatin (presumably via sst2 and sst4 receptors) appear to hold particular promise for anticonvulsive interventions. In addition, emerging gene therapy strategies employing viral vectors to enhance expression of endogenous anticonvulsant peptides are discussed. Collectively, seizure-induced plasticity of neuropeptide systems represents a significant component of the epileptic network and provides a rational basis for the development of novel antiepileptic and peptide-based gene therapeutic approaches.