Inhibitory Regulation of Dendritic Activity in vivo

Abstract

The spatiotemporal control of neuronal excitability is fundamental to the inhibitory process. We now have a wealth of information about the active dendritic properties of cortical neurons including axonally generated sodium action potentials as well as local sodium spikelets generated in the dendrites, calcium plateau spikes, and NMDA spikes. All of these events have been shown to be highly modified by the spatiotemporal pattern of nearby inhibitory input which can drastically change the output firing mode of the neuron. This means that particular populations of interneurons embedded in the neocortical microcircuitry can more precisely control pyramidal cell output than has previously been thought. Furthermore, the output of any given neuron tends to feed back onto inhibitory circuits making the resultant network activity further dependent on inhibition. Network activity is therefore ultimately governed by the subcellular microcircuitry of the cortex and it is impossible to ignore the subcompartmentalization of inhibitory influence at the neuronal level in order to understand its effects at the network level. In this article, we summarize the inhibitory circuits that have been shown so far to act on specific dendritic compartments in vivo.

Keywords: cortex; dendrite; inhibition; interneuron.

Figure 1

Sources of dendritic inhibition on neocortical pyramidal neurons. (A) Various inhibitory cell types and their axonal target regions on the pyramidal neuron’s dendritic tree. Adapted from (Benardo and Wong, 1995). (B) Electrogenic regions of the layer 5 neocortical pyramidal neurons. The dendritic regions which generate NMDA spike (red), Ca²⁺ spikes (blue), and Na²⁺ spikes (black) are color-coded (Larkum et al., 2009). (C) Schematic of the cortical network showing the relationship between long-range excitatory synaptic input, axonal projections of inhibitory neurons, and the layer 5 pyramidal neuron with its local electrogenic properties. Interneuron subclasses known to target dendrites and axons are schematically illustrated according to their layer specific distribution (colors corresponding to A). Seen from this perspective, axon terminations in different cortical lamina are likely to have specific influences on different spiking mechanisms within the pyramidal neurons [NMDA spike (red), Ca²⁺ spikes (blue), backpropagating APs (black), and axonal Na²⁺ spikes (green)].

Figure 2

Types of dendritic inhibition. (A) Ionotropic, GABA_A inhibition shunts the dendrites and spines via conductance of Cl⁻ and HCO₃ ions. GABA_B receptors on the other hand, which operate metabotropically, have a range of actions and locations. Presynaptically, one isoform of the receptor tends to block Ca²⁺ channels responsible for triggering the release mechanism. Postsynaptically, a different isoform of the GABA_B receptor opens G-protein activated inwardly rectifying K⁺ channels and blocks Ca²⁺ and NMDA channels that control dendritic electrogenesis. GABA_B receptors are found extrasynaptically where they are involved in “volume transmission” and tonic inhibition. (B) Martinotti neurons have been shown to mediate disynaptic inhibition between neocortical pyramidal neurons. Their apical dendrite targets the dendritic initiation zones of nearby pyramidal neurons (Silberberg and Markram, 2007). (C) Top, repetitive activation of Martinotti neurons causes brief and small hyperpolarizing potentials in the dendrites of pyramidal neurons but Ca²⁺ spikes generated by local dendritic depolarization (middle) are still powerfully blocked by GABA_A-mediated dendritic inhibition (bottom) because of the profound block of the underlying mechanisms for Ca²⁺ spikes (Murayama et al., 2009). (D) Late-spiking neurogliaform neurons of layer 1 also target the dendrites of cortical pyramidal neurons (Chu et al., 2003). (E) Neurogliaform cells mediate a large fraction of their inhibitory action on the dendrites through GABA_B receptors (Oláh et al., 2007).

Figure 3

Gain control via dendritic inhibition. (A) It has been postulated that inhibition of active dendritic conductances might act divisively, altering the slope or the gain of the f/I curve whereas inhibition of passive dendrites or somas would be predicted to be subtractive (simply shifting the curve, i.e., raising the threshold; Holt and Koch, 1997). Several systems reliant on pyramidal neurons have confirmed this hypothesis. (B) In the electric fish, one pathway (nP) targets the perisomatic region whereas another, feedback pathway (EGp) targets their active dendrites. A clear difference can be measured in terms of divisive versus subtractive inhibition in this system. Adapted from (Mehaffey et al., 2005). (C) Similarly, in the mammalian hippocampus, synaptic input is segregated on the dendritic trees of CA1 neurons where dendritic targeting somatostatin-positive inhibitory neurons have been shown to perform gain modulation whereas more proximal parvalbumin-positive neurons have negligible effect on gain. Adapted from (Lovett-Barron et al., 2012). (D) A similar effect of dendritic targeting, somatostatin-positive, Martinotti neurons of the neocortex was found from recordings in anesthetized rats. Here, deep-layer Martinotti neurons activated in a feedback loop with local L5 pyramidal neurons, control the gain of the f/I curve (Murayama et al., 2009).

Figure 4

Silent inhibition. (A) The tuning of subthreshold responses in cortical neurons driven by synaptic input in response to sensory stimuli can sometimes look very different to the suprathreshold spiking output which tends to be more narrowly tuned. In layer 2 pyramidal neurons of the visual cortex in mice, differently oriented visual stimuli cause very subtle differences in subthreshold responses but wildly different AP firing (Jia et al., 2010). (B) A similar phenomenon has been shown in somatosensory cortex of rodents where paired ipsi- and contralateral hindlimb stimuli (P-HS) lead to identical subthreshold responses to contralateral hindlimb stimuli (C-HS) alone whereas as spike output is different (Palmer et al., 2012). (C) In the somatosensory case, at least, it could be shown definitively that the difference was due to a form of dendritic GABA_B-mediated silent inhibition. This comes about because the inhibitory action is predominately on voltage-sensitive dendritic conductances. Without dendritic inhibition, AP firing in the neuron activates dendritic conductances which contribute to the integrative process in the production of subsequently generated APs. (D) Dendritic inhibition in the absence of cell firing opens dendritic K⁺ channels which have a very weak influence on the soma but their blocking action on dendritic Ca²⁺ channels is hidden or silent because these channels are closed anyway in the absence of dendritic depolarization. (E) Only during cell firing can the absence of the contribution from dendritic conductances be observed. Adapted from (Palmer et al., 2012).