Abstract
Dravet syndrome is a severe, childhood-onset epilepsy largely due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage-gated sodium (Na + ) channel α subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a +/- mice) indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons, in particular in parvalbumin-positive fast-spiking basket cell interneurons (PVINs). This has led to a model of Dravet syndrome pathogenesis in which Nav1.1 mutation leads to preferential dysfunction of interneurons, decreased synaptic inhibition, hyperexcitability, and epilepsy. However, such studies have been implemented at early developmental time points. Here, we performed electrophysiological recordings in acute brain slices prepared from male and female Scn1a +/- mice as well as age-matched wild-type littermate controls and found that, later in development, the excitability of PVINs had normalized. Analysis of action potential waveforms indirectly suggests a reorganization of axonal Na + channels in PVINs from Scn1a +/- mice, a finding supported by immunohistochemical data showing elongation of the axon initial segment. Our results imply that transient impairment of action potential generation by PVINs may contribute to the initial appearance of epilepsy, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 7912-7927 |
| Number of pages | 16 |
| Journal | Journal of Neuroscience |
| Volume | 38 |
| Issue number | 36 |
| DOIs | |
| State | Published - Sep 5 2018 |
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Keywords
- Dravet syndrome
- Epilepsy
- Fast-spiking interneurons
- Interneurons
- Nav1.1
- SCN1A
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
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A transient developmental window of fast-spiking interneuron dysfunction in a mouse model of dravet syndrome. / Favero, Morgana; Sotuyo, Nathaniel P.; Lopez, Emily; Kearney, Jennifer A.; Goldberg, Ethan M.
In: Journal of Neuroscience, Vol. 38, No. 36, 05.09.2018, p. 7912-7927.Research output: Contribution to journal › Article
TY - JOUR
T1 - A transient developmental window of fast-spiking interneuron dysfunction in a mouse model of dravet syndrome
AU - Favero, Morgana
AU - Sotuyo, Nathaniel P.
AU - Lopez, Emily
AU - Kearney, Jennifer A.
AU - Goldberg, Ethan M.
PY - 2018/9/5
Y1 - 2018/9/5
N2 - Dravet syndrome is a severe, childhood-onset epilepsy largely due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage-gated sodium (Na + ) channel α subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a +/- mice) indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons, in particular in parvalbumin-positive fast-spiking basket cell interneurons (PVINs). This has led to a model of Dravet syndrome pathogenesis in which Nav1.1 mutation leads to preferential dysfunction of interneurons, decreased synaptic inhibition, hyperexcitability, and epilepsy. However, such studies have been implemented at early developmental time points. Here, we performed electrophysiological recordings in acute brain slices prepared from male and female Scn1a +/- mice as well as age-matched wild-type littermate controls and found that, later in development, the excitability of PVINs had normalized. Analysis of action potential waveforms indirectly suggests a reorganization of axonal Na + channels in PVINs from Scn1a +/- mice, a finding supported by immunohistochemical data showing elongation of the axon initial segment. Our results imply that transient impairment of action potential generation by PVINs may contribute to the initial appearance of epilepsy, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.
AB - Dravet syndrome is a severe, childhood-onset epilepsy largely due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage-gated sodium (Na + ) channel α subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a +/- mice) indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons, in particular in parvalbumin-positive fast-spiking basket cell interneurons (PVINs). This has led to a model of Dravet syndrome pathogenesis in which Nav1.1 mutation leads to preferential dysfunction of interneurons, decreased synaptic inhibition, hyperexcitability, and epilepsy. However, such studies have been implemented at early developmental time points. Here, we performed electrophysiological recordings in acute brain slices prepared from male and female Scn1a +/- mice as well as age-matched wild-type littermate controls and found that, later in development, the excitability of PVINs had normalized. Analysis of action potential waveforms indirectly suggests a reorganization of axonal Na + channels in PVINs from Scn1a +/- mice, a finding supported by immunohistochemical data showing elongation of the axon initial segment. Our results imply that transient impairment of action potential generation by PVINs may contribute to the initial appearance of epilepsy, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.
KW - Dravet syndrome
KW - Epilepsy
KW - Fast-spiking interneurons
KW - Interneurons
KW - Nav1.1
KW - SCN1A
UR - http://www.scopus.com/inward/record.url?scp=85053083051&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053083051&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0193-18.2018
DO - 10.1523/JNEUROSCI.0193-18.2018
M3 - Article
C2 - 30104343
AN - SCOPUS:85053083051
VL - 38
SP - 7912
EP - 7927
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 36
ER -