Precision of Inhibition: Dendritic Inhibition by Individual GABAergic Synapses on Hippocampal Pyramidal Cells Is Confined in Space and Time

Abstract

Inhibition plays a fundamental role in controlling neuronal activity in the brain. While perisomatic inhibition has been studied in detail, the majority of inhibitory synapses are found on dendritic shafts and are less well characterized. Here, we combine paired patch-clamp recordings and two-photon Ca(2+) imaging to quantify inhibition exerted by individual GABAergic contacts on hippocampal pyramidal cell dendrites. We observed that Ca(2+) transients from back-propagating action potentials were significantly reduced during simultaneous activation of individual nearby inhibitory contacts. The inhibition of Ca(2+) transients depended on the precise spike-timing (time constant < 5 ms) and declined steeply in the proximal and distal direction (length constants 23-28 μm). Notably, Ca(2+) amplitudes in spines were inhibited to the same degree as in the shaft. Given the known anatomical distribution of inhibitory synapses, our data suggest that the collective inhibitory input to a pyramidal cell is sufficient to control Ca(2+) levels across the entire dendritic arbor with micrometer and millisecond precision.

Perisomatic GABAergic synapses of basket cells effectively control principal neuron activity in amygdala networks

“…This innervation pattern resembles the properties of neocortical basket cells, as they also innervate distal dendritic regions of PNs with several synapses (Tamás et al, 2000; Kubota et al, 2015; Kisvárday et al, 2002). The functional implication of the presence of both somatic and dendritic inhibitory inputs from the same cell requires more investigations, however, BCs in the BA -besides controlling action potential generation and somatic signal integration (present study)- might be able to influence local dendritic computations by innervating distal dendritic segments (Müllner et al, 2015). Our results thus may suggest that in the neocortical and amygdalar microcircuits, in sharp contrast to that observed in the hippocampus (Miles et al, 1996), BCs might have a dual function, as their output synapses are in the position to control both the input and output features of PNs.…”

“…The structural segregation of axon clouds of PV- and CCK-expressing GABAergic cells targeting distinct functional (perisomatic vs. dendritic) domains of pyramidal cells secures the division of labor between perisomatic and dendrite-targeting interneurons in the hippocampus. Perisomatic inhibitory interneurons effectively control the output, the spiking of pyramidal cells, while the dendritic interneurons regulate their input properties (Miles et al, 1996; Pouille et al, 2013; Müllner et al, 2015). This clear structural arrangement in axonal projections of interneurons is lacking in other cortical regions, and single BCs can innervate both the perisomatic region of PNs as well as their more distal dendrites (Jiang et al, 2015; Kubota et al, 2015; Kawaguchi and Kubota, 1998).…”

Norepinephrine and Corticotropin-Releasing Hormone: Partners in the Neural Circuits that Underpin Stress and Anxiety

“…Finally, the precise inhibition of backpropagating action potentials in dendrites observed by Mü llner et al (2015) highlights the importance of controlling bAPs as a key mechanism in certain forms of synaptic plasticity. Finally, the precise inhibition of backpropagating action potentials in dendrites observed by Mü llner et al (2015) highlights the importance of controlling bAPs as a key mechanism in certain forms of synaptic plasticity.…”

Dendritic Inhibitory Synapses Punch above Their Weight

“…Finally, the precise inhibition of backpropagating action potentials in dendrites observed byMü llner et al (2015) highlights the importance of controlling bAPs as a key mechanism in certain forms of synaptic plasticity. In particular, during STDP the backpropagating AP tells dendritic synapses whether they contributed successfully to generating the postsynaptic AP, implementing Hebb's rule.…”

“…Notably, both studies find that the effect on the bAP-boosting or inhibiting-depends on the local amplitude of the bAP. This suggests a mechanism, explored by Mü llner et al (2015) in a detailed model of CA1 pyramidal cells and illustrated using a simple ball-andstick model in Figure 1: the single inhibitory synapse hyperpolarizes the local membrane potential to prevent recruitment of voltage-gated channels that are responsible for the regenerative propagation of the bAP along the dendrite. Consequently, [Ca 2+ ] transients triggered by bAPs propagating just above the regenerative threshold can be reduced non-linearly if insufficient channels can be recruited due to the inhibition.…”