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Bidirectional GABAergic control of action potential firing in newborn hippocampal granule cells

Nature Neuroscience volume 19, pages 263–270 (2016)Cite this article

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Abstract

Newly generated young neurons in the adult hippocampus receive GABAergic synaptic inputs, which are crucial for activity-dependent survival and functional maturation between 1–3 weeks after mitosis. We found synaptically driven action potential (AP) firing in these newborn young cells in adult mice. Although glutamatergic synaptic inputs remained subthreshold, activation of GABAergic synaptic inputs depolarized young neurons and reliably evoked APs. Furthermore, pairing of subthreshold excitatory postsynaptic potentials or somatic current injection with brief bursts of GABAergic inputs revealed efficient GABAergic excitation at conductances of ∼1.5 nS, corresponding to the activity of only three or four interneurons. Stronger GABAergic inputs (>4 nS) effectively blocked AP firing via shunting inhibition, which might be important to dynamically control spiking output in both directions. Taken together, GABAergic interneurons differentially recruit newborn young granule cells by supporting either AP generation or shunting inhibition dependent on hippocampal network activity.

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Figure 1: GABAergic depolarization correlates with DCX-expression in hippocampal granule cells.
Figure 2: Bidirectional GABAergic control of action potential firing in immature hippocampal granule cells.
Figure 3: Efficient temporal integration of EPSPs and GPSPs.
Figure 4: GABA-induced excitation and inhibition of AP firing.
Figure 5: High GABAergic activity generates powerful shunting inhibition.
Figure 6: Dynamic shift from GABAergic excitation to shunting inhibition.

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Acknowledgements

We thank L. Aigner and S. Couillard-Despres (Paracelsus Medical University Salzburg, Austria) for originally providing the transgenic DCX-DsRed mice, J. Schulz for programming some of the Python-based data analysis, J. Schulz and L. Li for comments on the manuscript, S. Becherer for histochemical stainings and technical assistance, and M. Schwager for mouse genotyping. This work was supported by the Swiss National Science Foundation (SNSF, Project 31003A_153276).

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Authors and Affiliations

  1. Department of Biomedicine, University of Basel, Basel, Switzerland

    Stefanie Heigele & Josef Bischofberger

  2. Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland

    Sébastien Sultan & Nicolas Toni

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  1. Stefanie Heigele
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Contributions

J.B. and S.H. conceived and designed the experiments. S.H. conducted the experiments and analyzed the data. S.S. performed the viral injections. S.S. and N.T. critically reviewed and edited the manuscript. J.B. and S.H. wrote the paper.

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Correspondence to Josef Bischofberger.

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Integrated supplementary information

Supplementary Figure 1 Morphology and firing pattern of DCX+ young and mature hippocampal GCs in slices from the adult mouse brain.

(a) Confocal z-projection of a biocytin-filled (green) newborn granule cell with an input resistance of 9 GΩ. Small images of immunohistochemical stainings show double-labeling with strong DCX expression (red). (b) Ca2+-spike and AP induced by somatic current injection in a 9 GΩ granule cell. Minimal current for AP induction is indicated. (c) Decay after a small hyperpolarization revealed slow membrane time constant (τm = 186 ms, monoexponential fit in red). (d) Same as a for a 3 GΩ granule cell showing slightly advanced dendritic maturation and weaker DCX expression. (e) Firing pattern of the cell in d. (f) Voltage decay shows faster membrane time constant (τm = 94 ms). (g) Morphology of a mature DsRed-DCX- granule cell. (h) Mature firing pattern for the cell in g requires high current injection. (i) Voltage decay after the current pulse revealed a fast τm of 23 ms.

Supplementary Figure 2 Morphology and firing pattern of 2- and 3-week-old virus-labeled granule cells.

Differences in morphology, active and passive properties of granule cells at 2 (a-d) and 3 (e-h) weeks post injection (wpi). (a,e) Confocal z-projection of GFP+ neurons (green). (b,f) Biocytin filled somata (blue) with GFP (green) and DCX expression (red). (c,g) Firing pattern induced by current injection of the 2-wpi (c) and 3-wpi (g) virus-labelled GFP+ neuron shown in b and f, respectively. Minimal current for AP induction is indicated. (d,h) Monoexponential fit of the decay after a small hyperpolarizing current injection.

Supplementary Figure 3 Input resistance and membrane properties of developing granule cells change with cell age.

(a) Semi-logarithmic plot showing that input resistance (Rin) decreases with maturation. Green, individual GFP+ birth-dated granule cells. Black, mean ± s.e.m. of GFP+ neurons. ▼, 1 wpi. ■, 2 wpi. ▲, 3 wpi. ♦, 4 wpi. Red circle (mean ± s.e.m) shows Rin of recorded DCX-DsRed+ young granule cells. Red line indicates the range of the Rin of recorded DCX+ neurons (1.5–18 GΩ) corresponding to 1.5 to 3 weeks post mitosis. (b) Adult-born hippocampal granule cells loose DCX-expression at 3 wpi. (c-f) Semi-logarithmic plots of resting membrane potential (c), membrane time constant (d), threshold current to evoke an AP (e) and AP steepest slope (f) of DsRed+ young (red), DsRed− mature (black) and GFP+ birth-dated granule cells (green). Lines represent sigmoidal (c,d,f) or double exponential (e) fits.

Supplementary Figure 4 Gramicidin perforated-patch recordings in a DCX-DsRed+ hippocampal granule cell.

(a) DCX-DsRed+ young granule cells at the inner border of the granule cell layer. GCL, granule cell layer. H, hilus. (b,c) DsRed-fluorescence (b) and IR-DIC image (c) of a young DCX+ neuron in cell-attached mode. (d,e) Lucifer Yellow is restricted to the pipette during perforated-patch configuration (d) but clearly visible in the soma in whole-cell mode (e). (f) Scheme of different recording modes showing the separation of pipette solution from intracellular solution in the perforated patch configuration.

Supplementary Figure 5 Focal GABAergic stimulation does not induce APs in newborn DCX+ granule cells.

(a) Scheme depicting the position of the recording electrode and the stimulation electrode in the granule cells layer (GCL, blue) and molecular layer (ML, red). (b) Typical firing pattern of a young GC (top) in response to somatic current injection (bottom). (c) Postsynaptic response of a young GC to GCL burst stimulation in the presence of NBQX and AP5. (d) Postsynaptic response of a young GC to ML burst stimulation.

Supplementary Figure 6 AP threshold and latency after GABAergic and glutamatergic synaptic stimulation.

(a) Phase plot of an AP generated by synaptic stimulation in a young DCX+ granule cell. Inset, AP trace used for phase plot. Black, original data. Gray, after smoothing with a Savitzky-Golay filter (2nd order, 1 ms window width). (b) AP threshold and EGABA are similar in young granule cells (n = 13 and 10, p = 0.6330, Mann-Whitney U test) but highly different in mature neurons (n = 52 and 6, p < 0.0001, Mann-Whitney U test). (c) Numbers of spikes elicited by GABAergic and glutamatergic inputs at different latencies after ML-stimulation onset. Data were fitted with a Gaussian distribution. Inset, Representative trace of AP firing induced by combined GCL- and ML-stimulation from a holding potential of –80 mV. Stimulation protocol same as in Figure 6c(ii) with low GCL burst stimulation (blue) followed by ML stimulation (red). (d) Same as c for inputs mediated only by GABAergic synapses. (e) Overlay of Gaussian distributions of GABA + glutamate (red) and GABA-only (green) APs normalized to the integral. (f) Cumulative distribution of AP latencies. Scale bars represent 10 mV, 2.5 ms for a and 20 pA, 40 ms for c,d.

Supplementary Figure 7 Gramicidin perforated-patch recordings of GABAergic AP firing in newborn young granule cells.

(a-d) Five consecutive postsynaptic responses of a young DCX+ granule cell to electrical stimulation of ML and GCL synaptic inputs (n = 5). (a) Subthreshold PSPs induced by a double pulse in the ML (Δt = 10 ms, red). (b) Subthreshold PSPs induced by a burst stimulation in the GCL (8 times at 50 Hz, blue). (c) Pairing of ML and GCL stimulation effectively boosted AP firing. (d) A 3-fold increase in GCL stimulation intensity inhibits AP generation.

Supplementary Figure 8 Timing of GABAergic modulation of mock EPSPs in young and mature granule cells.

(a) Half-duration of GABA-PSP correlates with membrane time constant (p = 0.01, R2 = 0.47). (b) Optimal timing of mock EPSP with GABA-PSP to induce maximal AP probability correlates with membrane time constant (p = 0.0399, R2 = 0.3303). (c) Combined somatic current injection (green) and extracellular GCL stimulation (blue) in a mature GC in the presence of NBQX, AP5 and CGP. Mock PSP (22.0 ± 0.5 mV, n = 13) was shifted relative to GABA conductance. (d) Summary plot of PSP peak potentials at different delays relative to first stimulus. Reduction of PSP peak potential is prominent during GABAergic conductance (n = 13). (e) Combined somatic current injection and extracellular GCL stimulation in a young DCX+ GC in the presence of NBQX, AP5 and CGP. Mock PSP (23.3 ± 0.4 mV, n = 13) was shifted relative to GABA conductance. APs were cut for better illustration of subthreshold PSPs. (f) Summary plot of PSP peak potentials at different delays relative to first stimulus fitted with the product of two exponential functions (n = 13).

Supplementary Figure 9 Young granule cells show rapid capacitive current transients.

(a) Voltage response to a hyperpolarizing current pulse in a young granule cell. The capacitive current transient decays monoexponentially (red line). (b) Voltage response to a hyperpolarizing current pulse in a mature granule cell. The capacitive current transient decays biexponentially (red solid line). Dotted line represents a monoexponential fit.

Supplementary Figure 10 Scheme of GABAergic excitation and inhibition of AP firing.

(a) Presynaptic APs in glutamatergic fibers of the molecular layer (ML) generate EPSPs, which are too small to evoke APs in young granule cells. (b) Pairing of subthreshold PSPs in ML with a low number of active GABAergic synapses in the granule cell layer (GCL; 5-30% of GABAergic connections) will generate an axonal spike output. (c) Stronger GABAergic activity with more than 40% of synapses activated will effectively inhibit AP firing.

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Heigele, S., Sultan, S., Toni, N. et al. Bidirectional GABAergic control of action potential firing in newborn hippocampal granule cells. Nat Neurosci 19, 263–270 (2016). https://doi.org/10.1038/nn.4218

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