Development of dendritic tonic GABAergic inhibition regulates excitability and plasticity in CA1 pyramidal neurons

Abstract

Synaptic plasticity rules change during development: while hippocampal synapses can be potentiated by a single action potential pairing protocol in young neurons, mature neurons require burst firing to induce synaptic potentiation. An essential component for spike timing-dependent plasticity is the backpropagating action potential (BAP). BAP along the dendrites can be modulated by morphology and ion channel composition, both of which change during late postnatal development. However, it is unclear whether these dendritic changes can explain the developmental changes in synaptic plasticity induction rules. Here, we show that tonic GABAergic inhibition regulates dendritic action potential backpropagation in adolescent, but not preadolescent, CA1 pyramidal neurons. These developmental changes in tonic inhibition also altered the induction threshold for spike timing-dependent plasticity in adolescent neurons. This GABAergic regulatory effect on backpropagation is restricted to distal regions of apical dendrites (>200 μm) and mediated by α5-containing GABA(A) receptors. Direct dendritic recordings demonstrate α5-mediated tonic GABA(A) currents in adolescent neurons which can modulate BAPs. These developmental modulations in dendritic excitability could not be explained by concurrent changes in dendritic morphology. To explain our data, model simulations propose a distally increasing or localized distal expression of dendritic α5 tonic inhibition in mature neurons. Overall, our results demonstrate that dendritic integration and plasticity in more mature dendrites are significantly altered by tonic α5 inhibition in a dendritic region-specific and developmentally regulated manner.

Tonic GABAergic activity facilitates dendritic calcium signaling and short-term plasticity

“…Previous studies have clearly demonstrated a role for tonic GABAergic conductances in the steady suppression of neuronal output, mediated by both membrane hyperpolarization and shunting of synaptic inputs (Farrant and Nusser, 2005;Lee and Maguire, 2014). Indeed, a5 subunit-containing GABAARs were recently shown to suppress the backpropagation of APs in PN dendrites and the opening of NMDA-type glutamate receptors (Groen et al, 2014;Schulz et al, 2018). Our present results are not inconsistent with this view.…”

GABA-mediated tonic inhibition differentially modulates gain in functional subtypes of cortical interneurons

“…5g. Here, the presence of rectifying tonic inhibition attenuates electrotonic spread of AP's down the dendritic tree, as previously experimentally demonstrated in pyramidal neurons (28). This enhances the somato-dendritic voltage gradient and, by Ohm's law, also increases somato-dendritic current flow.…”

“…2b). The presence of non-rectifying tonic inhibition also induced significant differences in ∆ gain between fast spiking and non-fast spiking models, however differences were lower compared to rectifying tonic inhibition and increased gain within non-fast spiking models not observed (-5.4% ± 1.0 vs -0.7% ± 0.4, Welch's t-test, , t (28) = -4.4, **P < 0.001). We observed similar findings for EGABA of -80mV ( Supplementary Fig.…”

“…Tonic inhibition is thought to be mediated by ambient GABA acting diffusely upon the spatial extent of the neuronal membrane (1,28). Given our unexpected finding of differential gain modulation between fast spiking and non-fast spiking models, we next investigated how the spatial distribution of tonic inhibition impacts neuronal excitability.…”

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

“…By interfering with Ca 2+ -dependent processes by pharmacology and multi-synaptic stimulation (Meredith et al, 2003;Tsukada et al, 2005;Nishiyama et al, 2010;Groen et al, 2014), GABA A -receptor-mediated dendritic inhibition has been shown to modulate spike-timing-dependent plasticity rulessometimes even converting LTP-inducing into LTD-inducing stimuli. Addressing inhibition of Ca 2+ processes more directly, a number of elegant studies have described dendritic inhibition of Ca 2+ -dependent spikes upon activation of single (Larkum et al, 1999) or multiple (Miles et al, 1996;Tsubokawa and Ross, 1996) dendrite-targeting inhibitory interneurons in brain slices, as well as in vivo (Murayama et al, 2009).…”