Abstract
SummaryTraditionally, NMDA receptors are located postsynaptically; yet, putatively presynaptic NMDA receptors (preNMDARs) have been reported. Although implicated in controlling synaptic plasticity, their function is not well understood and their expression patterns are debated. We demonstrate that, in layer 5 of developing mouse visual cortex, preNMDARs specifically control synaptic transmission at pyramidal cell inputs to other pyramidal cells and to Martinotti cells, while leaving those to basket cells unaffected. We also reveal a type of interneuron that mediates ascending inhibition. In agreement with synapse-specific expression, we find preNMDAR-mediated calcium signals in a subset of pyramidal cell terminals. A tuned network model predicts that preNMDARs specifically reroute information flow in local circuits during high-frequency firing, in particular by impacting frequency-dependent disynaptic inhibition mediated by Martinotti cells, a finding that we experimentally verify. We conclude that postsynaptic cell type determines presynaptic terminal molecular identity and that preNMDARs govern information processing in neocortical columns.
Highlights
The neocortex is strikingly uniform, with extensive repetition of a limited number of circuit motifs (Douglas and Martin, 1998)
NMDA receptors (NMDARs) Blockade Selectively Suppresses excitatory postsynaptic potential (EPSP) onto pyramidal cells (PCs) but Not onto INs Prior studies in rat neocortex indicate that blockade of preNMDARs results in a reversible reduction of excitatory neurotransmission at monosynaptic connections between L5 PCs (Sjostrom et al, 2003), as well as at the L4-L2/3 path (Bender et al, 2006)
To investigate whether preNMDARs are differentially expressed in L5, we examined in mouse visual cortex the effect of the NMDAR antagonist AP5 on monosynaptic connections from L5 PCs onto L5 INs targeted based on their distinct small rounded somata (Figure 1A)
Summary
The neocortex is strikingly uniform, with extensive repetition of a limited number of circuit motifs (Douglas and Martin, 1998). These preNMDARs can impact both spontaneous and evoked neurotransmission in the short and intermediate term (Bardoni et al, 2004; Duguid and Smart, 2004; Sjostrom et al, 2003) but may play a role in the induction of long-term plasticity (Casado et al, 2002; Humeau et al, 2003; Sjostrom et al, 2003) Their presynaptic location, is peculiar, as it seems to render, e.g., NMDAR-based detection of coincident activity in connected neurons impossible without additional signaling from the postsynaptic side (Duguid and Sjostrom, 2006). This suggests that preNMDARs may serve other, presently unknown functions, pertinent to the functioning of the microcircuit
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