Biophysical Kv3 channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer’s
- Department of Cell Biology, Emory University, United States
- GDBBS Graduate Program, Laney Graduate School, Emory University, United States
- Department of Neurology, Emory University, United States
- Department of Biochemistry, Emory University, United States
- Stanley Center for Psychiatric Research, Broad Institute, United States
Figures
Figure 1 with 1 supplement
Reduced action potential (AP) firing frequency in parvalbumin (PV) interneurons of young 5xFAD mice.
(A) Graphical summary of AAV.E2.GFP stereotactic injection in somatosensory cortex and subsequent whole-cell current-clamp recordings from GFP+ PV interneurons (PV-INT). (B) AP firing elicited in …
Figure 1—figure supplement 1
Confirmation of parvalbumin (PV) interneuron gene expression in AAV.E2.GFP+ neurons.
(A) Depiction of cell-type-specific qPCR following stereotactic AAV injection in 5–6-week-old mice. ~200 GFP+ neurons were physically isolated and hand-picked from the somatosensory cortex at 7–8 …
Figure 2
Altered action potential (AP) waveforms in parvalbumin (PV) interneurons of 5xFAD mice.
(A) AP waveforms and properties of GFP+ interneurons were compared at 11 pA/pF square pulse injections in wild-type (WT) and 5xFAD mice. In the enlarged view, APs from the 1st and 20th spike in the …
Figure 3 with 1 supplement
Nav channel changes do not explain changes in parvalbumin (PV) interneuron excitability in 5xFAD mice.
(A) Depiction of PV cell single-compartmental model with modified Nav channel properties. (B) Simulated relationship (S/cm2) between the magnitude of injected current and action potential (AP) …
Figure 3—figure supplement 1
Nav channel changes do not explain changes in parvalbumin (PV) interneuron excitability in 5xFAD mice.
(A) Depiction of PV cell single-compartmental model with modified Nav channel properties. The relationship of injected current magnitude and action potential (AP) firing frequency with varying Nav …
Figure 4 with 2 supplements
Modified Kv3 channel biophysics in 5xFAD mice.
(A) Experimental workflow for obtaining outside-out patches from parvalbumin (PV) interneurons in wild-type (WT) and 5xFAD mice. (B) Representative Kv3 currents isolated from outside-out patches in …
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Figure 4—source data 1
Mass spectrometry of protein levels in 5xFAD mice.
- https://cdn.elifesciences.org/articles/75316/elife-75316-fig4-data1-v2.xlsx
Figure 4—figure supplement 1
Observed Kv3 inactivation properties and relationship to action potential (AP) firing in parvalbumin (PV) interneurons.
(A) Experimental workflow for obtaining outside-out patches from PV interneurons in wild-type (WT) and 5xFAD. (B) Representative tetraethylammonium (TEA)-sensitive currents (800 ms step; +50 mV …
Figure 4—figure supplement 2
Mass spectrometry (Mass Spec) of protein levels at varying ages in 5xFAD mice.
(A) Cartoon depiction of Mass Spec and data visualization. Rightward shifts indicate increases in protein levels while leftward shifts indicate decreases in protein levels in 5xFAD mice. (B–F) …
Figure 5 with 1 supplement
Effect of biophysical Kv3 dysregulation on action potential (AP) firing in a parvalbumin (PV) model.
(A) PV cell single-compartmental model with modified Kv3 channel properties. Kv3 activation voltage and kinetics were independently or simultaneously modified in the following simulations. When …
Figure 5—figure supplement 1
Effects of supplementing different Kv7 conductances on action potential (AP) firing in a parvalbumin (PV) model.
(A) PV cell single-compartmental model with Kv3 and additional Kv7 channels. Kv7 activation voltage and kinetics were independently or simultaneously modified. (B) AP firing elicited by square pulse …
Figure 6 with 1 supplement
Recapitulation of the 5xFAD phenotype in parvalbumin (PV) cells using dynamic clamp.
(A) Targeted dynamic clamp recordings from an AAV.E2.GFP+ neuron. Online Kv3 response (20 nS online gKv3) shown during action potential (AP) firing in a PV interneuron. (B) AP firing responses to …
Figure 6—figure supplement 1
Effects of wild-type (WT) and Alzheimer’s disease (AD) gKv3 dynamic clamp with endogenous Kv3 channels blocked.
(A) Targeted recordings from a representative E2.GFP+ parvalbumin (PV) interneuron. High-frequency action potential (AP) firing (current density 16 pA/pF) was evaluated in the same cell under …
Figure 7 with 1 supplement
Effect of 5xFAD-related Kv3 channel modulation on synaptically evoked action potential (AP) firing.
(A) Simulated responses of parvalbumin (PV) cell compartmental model with continuous excitatory and inhibitory inputs in control and with hyperpolarized Kv3 activation voltages. (B) Summary graph of …
Figure 7—figure supplement 1
Effect of 5xFAD-related Kv3 channel modulation on synaptically evoked subthreshold events.
(A) Average subthreshold response of parvalbumin (PV) cell compartmental model following excitatory input in control conditions and with a relative –10 mV Vshift in Kv3 activation voltage. (B) …
Figure 8 with 1 supplement
Hyperexcitability and increased gamma following parvalbumin (PV)-specific Kv3 modulation.
(A) Simplified cortical network consisting of 200 pyramidal cells (PC; triangles) and 20 PV (circle) cells. Connection probabilities between and within cell groups are set based on literature. …
Figure 8—figure supplement 1
Circuit synchronization following parvalbumin (PV)-specific Kv3 modulation.
(A) Membrane potential correlations within cell groups in control and –10 mV shifted gKv3 conditions. Correlations were measured as Pearson correlations coefficient comparing each individual cell. …
Tables
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Strain, strain background (Mus musculus) | Mouse: C57B6/J | Jackson Labs | Strain# 000664 | Wild-type mouse model |
| Strain, strain background (. musculus) | Mouse: 5xFAD C57B6/J | Jackson Labs | Strain # 032882 | ‘AD’ mouse model |
| Recombinant DNA reagent | AAV.E2.GFP | Original source: Jordane Dimidschstein (MIT) | Addgene 135631 | AAV construct to transfect and express GFP in PV cells |
| Chemical compound, drug | Tetraethylammonium (TEA) | Sigma-Aldrich | Cat# 86614 | Drug used to block Kv3 channels |
| Chemical compound, drug | Iberiotoxin (IBTX) | Alamone Labs | Cat# STI-400 | Drug used to block BK channels |
| Software, algorithm | NEURON simulation environment | https://neuron.yale.edu/neuron/ | Software for neuron and network simulations | |
| Software, algorithm | Dynamic clamp | Desai et al., 2008; Desai, 2022, https://github.com/nsdesai/dynamic_clamp | Software/hardware design for dynamic clamp system |
