Neurotensinergic augmentation of glutamate release at the perforant path-granule cell synapse in rat dentate gyrus: Roles of L-Type Ca2+ channels, calmodulin and myosin light-chain kinase

•NT persistently increases glutamate release at PP-GC synapse in dentate gyrus.•The effect of NT is mediated by presynaptic NTS1 receptors.•NT increases the release probability and the number of readily releasable vesicles.•Ca2+ influx via L-type Ca2+ channels is involved.•Functions of calmodulin and myosin light chain kinase are required.

Neurotensin (NT) serves as a neuromodulator in the brain where it is involved in modulating a variety of physiological functions including nociception, temperature, blood pressure and cognition, and many neurological diseases such as Alzheimer's disease, schizophrenia and Parkinson's disease. Whereas there is compelling evidence demonstrating that NT facilitates cognitive processes, the underlying cellular and molecular mechanisms have not been fully determined. Because the dentate gyrus expresses high densities of NT and NT receptors, we examined the effects of NT on the synaptic transmission at the synapse formed between the perforant path (PP) and granule cells (GC) in the rats. Our results demonstrate that NT persistently increased the amplitude of the AMPA receptor-mediated EPSCs at the PP-GC synapse. NT-induced increases in AMPA EPSCs were mediated by presynaptic NTS1 receptors. NT reduced the coefficient of variation and paired-pulse ratio of AMPA EPSCs suggesting that NT facilitates presynaptic glutamate release. NT increased the release probability and the number of readily releasable vesicles with no effects on the rate of recovery from vesicle depletion. NT-mediated augmentation of glutamate release required the influx of Ca2+ via L-type Ca2+ channels and the functions of calmodulin and myosin light chain kinase. Our results provide a cellular and molecular mechanism to explain the roles of NT in the hippocampus.