Substance P (SP), a neuropeptide that belongs to the tachykinin family, is widely distributed of the mammalian hippocampus together with its binding sites. In this particular brain region in the rat SP has been implied in early neuronal development, facilitation of learning and seizure activity (Huston and Hasenohrl, I995; Sprick et al., I996, Taoka et al., I996; Sperk et al., I990). Up to now no systematic electrophysiological analysis has been undertaken to characterise its cellular effects on hippocampal neurones unlike for example the work done on the spinal cord, where its neurotransmitter role is well established (for review Otsuka and Yoshioka, I993). In the present study the effects produced by bath application of SP (2-4 μM) or the selective NK1 receptor agonist substance P methylester (SPME; 10 nM-5 μM) were investigated employing intra- or extracellular recordings from the CAI region of the mouse hippocampal slice preparation. Field potentials evoked by focal electrical stimulation of Schaffer collaterals and recorded from stratum pyramidale were depressed in the presence of the neuropeptide. This effect was NK1 receptor mediated as it was completely blocked by the selective NK1 antagonist SRI40333, and it required an intact GABAergic network drive. The evoked excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) recorded from CAI pyramidal neurones were similarly depressed by SPME. At the same time this neuropeptide increased the frequency (but not the size) of spontaneous GABAergic events and reduced the frequency of spontaneous glutamatergic events. Both effects of SPME on spontaneous and evoked IPSPs were prevented by the ionotropic glutamate receptor blocker kynurenic acid. No changes in frequency or size of spontaneous events produced by SPME were evident in TTX solution. The responses of pyramidal cells to 4 μM AMP A or 10 μM NMDA were not altered by SPME. To investigate the modulatory effect of SPME on cholinergic synaptic transmission in the hippocampus, brief (1-2 min) application of CCh (0.1 μM-100 μM) or electrical stimulation at the stratum oriens/alveus border was utilized. The observed excitatory response consisted of membrane potential depolarization, input resistance increase (or no change), bicuculline-sensitive repetitive oscillatory activity and slow synchronized events, which were supposed to be mediated via Ml muscarinic receptor subtype, as they were reversibly blocked by pirenzepine and by atropine in irreversible manner. All the components of this cholinergic response were potentiated in a dose dependent and· SR 140333 sensitive manner by pre-application of SPME. The enhancement by SPME of depolarization produced by CCh application was present (albeit attenuated) in TIX solution. By itself SPME produced minimal changes in passive membrane properties of CAI pyramidal cells, which were unable to account for the observed effects on fast and slow synaptic transmission. The present data indicate that on CAI pyramidal neurones SPME exerted its action via a complex network mechanism, which presumably involved facilitation of a population of GABA-ergic intemeurones widely interconnected with excitatory and inhibitory cells in this hippocampal region.
|Titolo:||An electrophysiological study of the effects of substance P on CA1 neurones of the mouse hippocampal slice preparation|
|Data di pubblicazione:||28-mag-1999|
|Appare nelle tipologie:||8.1 PhD thesis|