Geometric principles of dendritic integration of excitation and inhibition in cortical neurons

We use two-color uncaging of glutamate and γ-aminobutyric acid (GABA) on layer 5 (L5) pyramidal neurons of the cingulate cortex to define how inhibitory control of excitation is determined by dendritic geometry. Traditionally, GABAergic input was considered as the gatekeeper; thus, receptors closest to the soma were ideally placed to veto excitation. However, recently modeling has advanced several counterintuitive hypotheses. Since laser uncaging can be directed at will to any position, we used photostimulation to show that inhibition near the sealed end of dendrites distal to excitation is more effective than inhibition near the soma in modulating excitation. Further, dendritic inhibition was found to be branch specific. Last, we demonstrate that inhibitory input from multiple thin basal dendrites can centripetally elevate to effectively tune distant excitation at the soma. These findings provide direct experimental evidence supporting theoretical predictions based on dendritic cable properties, revealing the critical role of dendritic geometry in shaping the interaction between excitatory and inhibitory neurotransmission.