Deliverables
Today it is widely accepted that learning and memory are mediated by changes in synaptic efficiency of which the most prominent example is long-term potentiation (LTP) of synaptic responses in the hippocampus. This project aimed to investigate the role of selected neuropeptides, which are suggested to act as modulators of cognition, in the regulation of hippocampal synaptic plasticity, and to elucidate the underlying mechanisms of this regulation.
Although arginine-vasopressin AVP(4-9) and its metabolites belong to the best investigated neuropeptides with respect to learning and memory the detailed mechanisms underlying their action on synaptic plasticity were still unknown. We found that bath-application of AVP(4-9) could induce a slight (about 20%), gradually developing long-term enhancement of the CA1 field EPSPs. in for 15-20 min. This enhancement was insensitive NMDA-independent and thus differed from tetanus-induced LTP. A similar enhancement could be induced by the short derivative AVP(4-5). Results obtained with isolated CA1 pyramidal cells indicated that AVP(4-9) can modulate transmembrane currents activated by the AMPA- but not by the NMDA-subtype of glutamate receptors. The potentiation of AMPA-induced responses developed within 4-6 min after a 20s-application of AVP(4-9) and lasted up to 20 min. The AVP(4-9) interaction with AMPA-induced currents was specific for the hippocampal pyramidal cells since none of the tested cerebellar Purkinje cells revealed any modulation of AMPA-induced responses.
Galanin is a peptide which is co-localized with acetylcholine in neurons of the basal forebrain which project inter alia to the hippocampus. Recent studies indicate, that galanin plays an inhibitory role in hippocampus-dependent learning and memory processes. We found that bath-application of galanin (200 nM or 1µM) 30 min prior to tetanization and up to 10 min thereafter resulted in a higher potentiation of the population-spike amplitude, but left the potentiation of the fEPSP slope untouched. This holds true of whether a weak or a strong tetanization was used to induce LTP. The selective galanin-receptor inhibitor M35 (40 nM) did not show an effect on potentiation induced by strong tetanic stimulation, but impaired an LTP generated by a weak tetanus.
The effects of thyrotropin releasing hormone (pGlu-His-Pro) on synaptic plasticity in the CA1-region were studied using a weak (100Hz, 10 or 30 pulses) and a strong tetanus protocol (100Hz, 100 pulses) . TRH (0.1 - 5µM) introduced into the perfusion medium 15 min before tetanus did not significantly change an LTP induced by the weak tetanus but completely blocked the development of LTP after a strong tetanization. This effect was not dose-dependent within the concentration range from 5nM to 10µM (5nM, 50nM, 0.5uM, 1µM and 10µM). The experiments on isolated CA1 pyramidal cells showed that TRH in micromolar concentrations may induce slow inward currents in some pyramidal cells, which is indicative of the presence of functional receptors. However, the low incidence of such currents hampered further analysis of their nature. In none of the cells recorded, TRH application modified the currents activated by either glutamate receptor agonists or GABA. These data suggest that TRH does not interact with extracellular sites of these receptors.
Corticotropin-like intermediate lobe peptide (CLIP; ACTH18-39) belongs to the family of POMC-derived peptides which have been implicated in a broad array of physiological functions. However, little is known about the physiological significance of this peptide so far. In experiments in the dentate gyrus of freely-moving rats we observed that CLIP given at a dose of 20 ng i.c.v. impaired LTP. Under the same conditions, an N-terminal fragment of CLIP (ACTH 18-24) displayed a similar action whereas ACTH 1-39 had no effect. The same dose of CLIP also resulted in a deterioration of hippocampus-dependent learning. These studies suggest that the biologically active sequence of CLIP is contained in the N-terminus and implicate CLIP-derived peptides in synaptic plasticity and learning.
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