Neuromodulatory systems of the brain have been suggested to profoundly impact on neurotransmission and long-term synaptic plasticity, the cellular correlate for learning and memory. The cerebellum, involved in procedural memory, receives abundant cholinergic innervation and shows a dense nicotinic acetylcholine receptor (nAChRs) expression. However, the functional effects of nAChRs in the cerebellum are still largely unknown. To address this issue we have performed voltage-clamp recordings in whole cell configuration in the granular layer of acute slices obtained from the cerebellar vermis of P18-P22 rats. A 100-sec application of nicotine (1M) significantly enhanced glutamatergic EPSCs. The effect was transient, suggesting that nAChR were progressively desensitizing.AsnAChRsareoftenlocatedinthepresynaptic terminals where they modulate other neurotransmitter release we have therefore investigated whether a similar mechanism could operate in the cerebellum. EPSCs mediated by AMPA receptors were elicited in pairs with an interpulse interval of 20ms. Nicotine exposure readily caused a reduction of the pair pulse ratio (PPR). Moreover, a high calcium buffer concentration in the intracellular solution was still accompanied by a significant PPR decrease during nicotine application supporting its presynaptic origin. EPSCs mediated by NMDA receptors were not influenced by nicotine. Interestingly, when a high calcium buffer concentration was added to the intracellular solution, the effect of nicotine was restored and NMDA EPSCs increased. Therefore, nicotine could act both pre- and postsynaptically. The enhancement of neurotransmission caused by nicotine suggested that nicotine could also enhance the induction of LTP. We therefore tested whether a single100ms/100Hzburst,whichdeterminesalong-termdepression of EPSC peak could turn into LTP induction in the presence of nicotine. Exposure to 1M nicotine led the development of LTP of the EPSCs following the 100ms/100Hz burst. To explore which nAChR subtype mediated the facilitating effect of nicotine on LTP, recordings were performed in the presence of 7 nAChR agonist and antagonist: choline (10 mM) and MLA (100 nM), respectively. The application of choline (100 s) increased the EPSC and then a single 100 ms/100 Hz burst led to LTP. The co-application of nicotine with MLA (100 s) prevented switching form LTD to LTP. These results suggest that cholinergic stimulation mediated by nAChRs markedly potentiates synaptic transmission and long term synaptic plasticity along the mossy fibre pathway of the cerebellum.
Nicotinic receptor activation increases glutamatergic transmission and plasticity in the rat cerebellum
Prestori F;D'angelo E.
2009-01-01
Abstract
Neuromodulatory systems of the brain have been suggested to profoundly impact on neurotransmission and long-term synaptic plasticity, the cellular correlate for learning and memory. The cerebellum, involved in procedural memory, receives abundant cholinergic innervation and shows a dense nicotinic acetylcholine receptor (nAChRs) expression. However, the functional effects of nAChRs in the cerebellum are still largely unknown. To address this issue we have performed voltage-clamp recordings in whole cell configuration in the granular layer of acute slices obtained from the cerebellar vermis of P18-P22 rats. A 100-sec application of nicotine (1M) significantly enhanced glutamatergic EPSCs. The effect was transient, suggesting that nAChR were progressively desensitizing.AsnAChRsareoftenlocatedinthepresynaptic terminals where they modulate other neurotransmitter release we have therefore investigated whether a similar mechanism could operate in the cerebellum. EPSCs mediated by AMPA receptors were elicited in pairs with an interpulse interval of 20ms. Nicotine exposure readily caused a reduction of the pair pulse ratio (PPR). Moreover, a high calcium buffer concentration in the intracellular solution was still accompanied by a significant PPR decrease during nicotine application supporting its presynaptic origin. EPSCs mediated by NMDA receptors were not influenced by nicotine. Interestingly, when a high calcium buffer concentration was added to the intracellular solution, the effect of nicotine was restored and NMDA EPSCs increased. Therefore, nicotine could act both pre- and postsynaptically. The enhancement of neurotransmission caused by nicotine suggested that nicotine could also enhance the induction of LTP. We therefore tested whether a single100ms/100Hzburst,whichdeterminesalong-termdepression of EPSC peak could turn into LTP induction in the presence of nicotine. Exposure to 1M nicotine led the development of LTP of the EPSCs following the 100ms/100Hz burst. To explore which nAChR subtype mediated the facilitating effect of nicotine on LTP, recordings were performed in the presence of 7 nAChR agonist and antagonist: choline (10 mM) and MLA (100 nM), respectively. The application of choline (100 s) increased the EPSC and then a single 100 ms/100 Hz burst led to LTP. The co-application of nicotine with MLA (100 s) prevented switching form LTD to LTP. These results suggest that cholinergic stimulation mediated by nAChRs markedly potentiates synaptic transmission and long term synaptic plasticity along the mossy fibre pathway of the cerebellum.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
