Dendritic NMDA spikes are necessary for timing-dependent associative LTP in CA3 pyramidal cells

Abstract

The computational repertoire of neurons is enhanced by regenerative electrical signals initiated in dendrites. These events, referred to as dendritic spikes, can act as cell-intrinsic amplifiers of synaptic input. Among these signals, dendritic NMDA spikes are of interest in light of their correlation with synaptic LTP induction. Because it is not possible to block NMDA spikes pharmacologically while maintaining NMDA receptors available to initiate synaptic plasticity, it remains unclear whether NMDA spikes alone can trigger LTP. Here we use dendritic recordings and calcium imaging to analyse the role of NMDA spikes in associative LTP in CA3 pyramidal cells. We show that NMDA spikes produce regenerative branch-specific calcium transients. Decreasing the probability of NMDA spikes reduces LTP, whereas increasing their probability enhances LTP. NMDA spikes and LTP occur without back-propagating action potentials. However, action potentials can facilitate LTP induction by promoting NMDA spikes. Thus, NMDA spikes are necessary and sufficient to produce the critical postsynaptic depolarization required for associative LTP in CA3 pyramidal cells.

Increased Prevalence of Calcium Transients across the Dendritic Arbor during Place Field Formation

“…If synaptic plasticity is occurring during this delay period to contribute to the formation of new place fields, it appears to occur in the absence of somatic action potential firing and back-propagation into the dendrites. We therefore looked for dendrite-localized calcium transients that might result from local clustered synaptic input (possibly generating local regenerative events) capable of inducing synaptic potentiation in the absence of somatic firing (Brandalise et al, 2016; Losonczy and Magee, 2006; Major et al, 2008; Milojkovic et al, 2007; Oakley et al, 2001; Palmer et al, 2014; Schiller et al, 2000; Weber et al, 2016; Wei et al, 2001). …”

“…We used established glutamate uncaging techniques to mimic synaptic inputs at selected spines along a single basal dendrite of a CA1 neuron expressing GCaMP6f (Bloodgood and Sabatini, 2007; Losonczy and Magee, 2006; Losonczy et al, 2008). Using a 2-photon microscope to image dendrites during spine stimulation, we found that simultaneous (within 5 ms) clustered input within 5–15 μm onto multiple spines (3 or more) often generated dendritic calcium transients that spread beyond the stimulated spines and into the nearby shaft (Figure S3D), a signature suggesting local dendritic spike generation (Brandalise et al, 2016; Losonczy and Magee, 2006; Major et al, 2008; Milojkovic et al, 2007; Oakley et al, 2001; Palmer et al, 2014; Schiller et al, 2000; Weber et al, 2016; Wei et al, 2001). These dendrite-localized calcium transients stimulated in slice had transient amplitudes and durations similar to the dendrite-localized transients recorded during the delay period of delayed onset place fields in behaving mice (Figure S3).…”

Glutamatergic synapses are structurally and biochemically complex because of multiple plasticity processes: long-term potentiation, long-term depression, short-term potentiation and scaling

“…Importantly, in some cases, the dendritic depolarizing event responsible for LTP induction has been identified both in slice experiments and in vivo [13,[15][16][17]. These studies point to the importance of branch-specific long-duration spikes mediated by NMDA channels.…”

“…These studies point to the importance of branch-specific long-duration spikes mediated by NMDA channels. In CA3, Na spikes can sometimes trigger NMDA spikes, particularly if the Na spikes occur in bursts [16]. It is therefore now clear that STDP, a process that assumes that only Na spikes determine LTP/LTD, is an incorrect description of plasticity.…”

Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability

“…Action potentials are not a reliable indication of learning-related events because they can result from the activity of previously potentiated synapses. Similarly, LTP events at the synapse are not a reliable indicator that a cell should be part of a new ensemble because LTP can occur in a dendritic branch without somatic sodium spikes 57,58 . Making a cell fire, and thus able to be incorporated into an ensemble, may require that multiple branches undergo synaptic plasticity.…”