HCN channels regulate excitability and gate synaptic amplification via NMDA in mouse L2/3 pyramidal neurons

Layer 2/3 pyramidal cells (L2/3 PCs) play a crucial role in cortical information transfer. Although the dendritic arbors of L2/3 PCs are impressive, they lack the distinct anatomical compartments characteristic of deeper L5 PCs. For example, many L2/3 PCs do not display an apparent distal tuft region. However, L2/3 PCs receive inputs from both thalamic (bottom-up) and cortical (top-down) inputs, preferentially synapsing onto their proximal and distal dendrites, respectively. Nonuniform organization of channels and NMDA receptors in L2/3 dendrites could serve to independently modulate these information streams to affect learning and behavior, yet whether L2/3 PC dendrites possess this capability has not been established. Here, we found a previously unappreciated non-uniform HCN channel distribution in L2/3 PCs, allowing for pathway-specific gating of NMDA receptor recruitment at bottom-up (proximal) but not top-down (distal) synapses. Interestingly, HCN availability could be regulated via neuromodulation, suggesting that the gain of thalamic and cortical-cortical signals in L2/3 may be independently modified in vivo.