Interneuron Loss in a Mouse Model of DNM1-mediated Epileptic Encephalopathy
Conference Year
January 2020
Abstract
The human DNM1 gene has recently been associated with the development of early onset, severe seizure disorders known as epileptic encephalopathies (EEs). In mice, the Dnm1 gene was also shown to cause seizures following an A408T missense mutation, known as “Fitful.” These Fitful mice have seizures and die by weaning age. Previous work has shown that the presence of the Fitful mutation in various interneuron subtypes is particularly detrimental to the animals survival, while the Fitful mutation in excitatory neurons causes behavioral abnormalities, but no overt health problems.
To begin to clarify why the presence of the Fitful mutation in interneurons is so detrimental, we performed immunohistochemistry on tissue taken from postnatal day 14 mice and labeled parvalbumin and somatostatin positive (PV+ and SST+) interneurons. We found that homozygous Fitful mice have dramatically reduced numbers of PV+ and SST+ interneurons relative to wild-type controls. Similarly, heterozygous mice show slightly reduced PV+ interneuron number relative to controls. Additionally, heterozygous mice show little to no reduction in SST+ interneuron number. Together, this suggests that interneurons are vulnerable to Dnm1 mutation, and that SST+ interneurons are more vulnerable than PV+ interneurons. Future work will be needed to determine if other interneuron subtypes are similarly affected, and whether the reduction in interneuron number occurs due to issues with interneuron proliferation, migration, or survival.
Primary Faculty Mentor Name
Matthew Weston
Secondary Mentor Name
Matthew McCabe
Graduate Student Mentors
Matthew McCabe
Faculty/Staff Collaborators
Matthew McCabe, Amy Shore, Wayne Frankle, Matthew Weston
Status
Undergraduate
Student College
College of Arts and Sciences
Program/Major
Neuroscience
Primary Research Category
Biological Sciences
Interneuron Loss in a Mouse Model of DNM1-mediated Epileptic Encephalopathy
The human DNM1 gene has recently been associated with the development of early onset, severe seizure disorders known as epileptic encephalopathies (EEs). In mice, the Dnm1 gene was also shown to cause seizures following an A408T missense mutation, known as “Fitful.” These Fitful mice have seizures and die by weaning age. Previous work has shown that the presence of the Fitful mutation in various interneuron subtypes is particularly detrimental to the animals survival, while the Fitful mutation in excitatory neurons causes behavioral abnormalities, but no overt health problems.
To begin to clarify why the presence of the Fitful mutation in interneurons is so detrimental, we performed immunohistochemistry on tissue taken from postnatal day 14 mice and labeled parvalbumin and somatostatin positive (PV+ and SST+) interneurons. We found that homozygous Fitful mice have dramatically reduced numbers of PV+ and SST+ interneurons relative to wild-type controls. Similarly, heterozygous mice show slightly reduced PV+ interneuron number relative to controls. Additionally, heterozygous mice show little to no reduction in SST+ interneuron number. Together, this suggests that interneurons are vulnerable to Dnm1 mutation, and that SST+ interneurons are more vulnerable than PV+ interneurons. Future work will be needed to determine if other interneuron subtypes are similarly affected, and whether the reduction in interneuron number occurs due to issues with interneuron proliferation, migration, or survival.