, 2004 and Steinert et al , 2010) We therefore have no reason to

, 2004 and Steinert et al., 2010). We therefore have no reason to advocate anything unique about

the kinetic performance of hippocampal presynaptic NMDARs. Focal release of caged glutamate was also used to explore whether NMDAR currents might be detected outside the region of the bouton. Because we find this to not be the case, it appears that the receptor density is highest at boutons. This result is important because it indicates that the large amplitude Ca2+ transients we observe at boutons do not arise as an anomaly of Ca2+ imaging, dyes, or cellular buffers, but are a robust measure of Ca2+ influx at that site. Direct evidence for NMDA autoreceptors in the hippocampus is new; however, evidence linking NMDAR autoregulatory release in plasticity is described in other brain areas. Presynaptic NMDARs are implicated in the modulation of LTD in the visual cortex (Sjöström et al., 2003), cerebellum (Casado et al., 2002 and Duguid and SB431542 manufacturer Smart, 2004), selleck kinase inhibitor and barrel cortex (Rodíguez-Moreno and Paulsen, 2008). Interestingly, little evidence exists linking presynaptic NMDARs to LTP. In fact, Rodríguez-Moreno and Paulsen (2008) report that in barrel cortex, the type of plasticity expressed, LTD or LTP, is linked to whether pre- or postsynaptic

NMDARs are activated. Our data suggest that presynaptic NMDARs serve to facilitate transmission at theta frequency and are therefore likely to augment the induction of LTP. Analysis of Ca2+ transients evoked by single spikes provides little information about the stimulus conditions under which augmentation of the Ca2+ signal might alter transmitter release. We therefore measured transmitter release in response to different from stimulus frequencies. We found that presynaptic NMDAR activation produced robust facilitation of transmission during theta frequency and that although stimulation at higher frequencies also facilitates the amplitude of the postsynaptic current, the facilitation is insensitive to D-AP5. Presynaptic NMDARs serve

to augment transmitter release at theta frequency, but when the frequency of APs reaches 20 Hz, Ca2+ entry through VDCCs occurs with such rapidity that the bouton becomes progressively more Ca2+ loaded, that is, Ca2+ entry exceeds clearance. Our search to understand the basis of Ca2+ transient variance serendipitously led us to identify a novel way to measure pr. We therefore sought to verify that large Ca2+ events signaled transmitter release. We show that large events, like pr, are heterogenous between boutons. This has additional significance because it illustrates that the electrotonic spread of NMDAR-mediated depolarization elicited in the dendrites, as reported for cerebellar interneurons (Christie and Jahr, 2008), cannot be responsible for the NMDAR-mediated large Ca2+ transients seen here, because large events occur at some boutons but not others along the same axon in response to the same AP.

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