Scientific Understanding of Consciousness
Dendritic Spines GABAergic Inhibition Shapes Neuronal Activity
Science 10 May 2013: Vol. 340 no. 6133 pp. 759-762
Compartmentalization of GABAergic Inhibition by Dendritic Spines
Chiayu Q. Chiu, Gyorgy Lur, Thomas M. Morse, Nicholas T. Carnevale, Graham C. R. Ellis-Davies, Michael J. Higley
1Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA.
2Yale Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, CT 06510, USA.
3Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
γ-aminobutyric acid–mediated (GABAergic) inhibition plays a critical role in shaping neuronal activity in the neocortex. Numerous experimental investigations have examined perisomatic inhibitory synapses, which control action potential output from pyramidal neurons. However, most inhibitory synapses in the neocortex are formed onto pyramidal cell dendrites, where theoretical studies suggest they may focally regulate cellular activity. The precision of GABAergic control over dendritic electrical and biochemical signaling is unknown. By using cell type-specific optical stimulation in combination with two-photon calcium (Ca2+) imaging, we show that somatostatin-expressing interneurons exert compartmentalized control over postsynaptic Ca2+ signals within individual dendritic spines. This highly focal inhibitory action is mediated by a subset of GABAergic synapses that directly target spine heads. GABAergic inhibition thus participates in localized control of dendritic electrical and biochemical signaling.
A challenge to elucidating the function of synaptic inhibition is the diversity of GABAergic interneurons found in cortical circuits. Several interneuron classes, including those that express somatostatin (SOM-INs), target the dendrites of excitatory, glutamatergic pyramidal cells. SOM-INs regulate the initiation of action potential bursts generated via active currents in postsynaptic dendrites. We hypothesized that these inputs might also exert focal influence over dendritic signaling. Here, we used electrophysiological, optical, and computational approaches to investigate the localized actions of GABAergic inhibition in pyramidal cell dendrites.
To activate dendritic GABAergic synapses, we used a somatostatin-Cre mouse line to conditionally express channelrhodopsin-2 (ChR2) in SOM-INs of the prefrontal cortex. In acute brain slices prepared 2 to 3 weeks after viral injection, pulses of light (5 ms, 473 nm) delivered through the microscope objective evoked action potentials (APs) in fluorescently identified SOM-Ins. Whole-cell recordings in layer 2/3 pyramidal neurons revealed corresponding inhibitory postsynaptic potentials (IPSPs).
To determine how inhibition influences dendritic activity in pyramidal neurons, we used two-photon laser scanning microscopy (2PLSM) to image calcium (Ca2+) in apical dendritic spines and shafts.
We frequently observed inhibited and uninhibited spines in close proximity, suggesting compartmentalized GABAergic control of Ca2+ signaling. We therefore imaged Ca2+ inhibition within a small dendritic region. Spines adjacent to an inhibited reference spine typically showed little modulation despite the presence of a somatic IPSP. We generated “maps” demonstrating heterogeneous inhibition over short distances. There was significantly greater inhibition for each reference spine than for its adjacent neighbor (0.58 ± 0.03 versus 0.82 ± 0.03, P < 0.001, n = 22 maps), and inhibition between neighbors was not correlated (Pearson r2 = 0.12, P = 0.09).
Inhibition was stronger in spines than in dendritic shafts (0.65 ± 0.02 versus 0.79 ± 0.03, P < 0.0001, n = 59)
The magnitude of inhibition was influenced by spine neck resistance.
Results indicate that dendritic spines compartmentalize GABAergic inhibition, limiting both AP- and synaptically evoked Ca2+ influx and regulating NMDAR-dependent synaptic integration.
Experimental data demonstrated that GABA receptors can inhibit regenerative voltage-dependent dendritic spikes, controlling the production of AP bursts at the soma. These findings were mediated in part by GABAB-dependent modulation of VGCCs and NMDARs and suggested that inhibition acts with lower spatial resolution than glutamatergic excitation, which exhibits compartmentalization of electrical and biochemical signals within single spines. However, our data indicate that the spine head similarly restricts GABAA-mediated inhibition. The model further suggests that, in addition to the chloride reversal potential, spine neck resistance influences the efficacy of GABAergic synapses onto spine heads as occurs for glutamatergic inputs. Notably, our experimental data was closely modeled by using a neck resistance of 520 Mohm, similar to the value reported for hippocampal pyramidal neurons. Both neck resistance and chloride reversal are modulated by development and experience, suggesting the impact of dendritic inhibition may be similarly regulated.
Dendritic Ca2+ influx plays a key role in the induction of plasticity at glutamatergic synapses, and inhibition can serve as a negative regulator of plasticity. Our results suggest that this control occurs at a previously unappreciated spatial scale, enabling dendrite-targeting interneurons to influence individual glutamatergic inputs. This observation is particularly relevant given the growing attention to links between perturbed GABAergic inhibition, alterations in developing neuronal circuits, and neuropsychiatric disorders such as schizophrenia and autism.
Why do certain spines receive GABAergic inputs? One possibility is that GABA receptors are recruited by the presence of specific glutamatergic afferents, as proposed for thalamorecipient spines in frontal or visual cortex. Additionally, recruitment of GABAA receptors might be activity-dependent. This hypothesis is supported by evidence that spine-targeting GABAergic inputs exhibit distinctly high rates of turnover in vivo. Future experiments are necessary to determine the existence of feedback loops between dendritic Ca2+ signals and the formation and stabilization of GABAergic synapses.
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