TY - JOUR
T1 - Effects of altered tau expression on dentate granule cell excitability in mice
AU - Cloyd, Ryan A.
AU - Koren, John
AU - Abisambra, Jose F.
AU - Smith, Bret N.
N1 - Publisher Copyright:
© 2021
PY - 2021/9
Y1 - 2021/9
N2 - Tauopathies, including Alzheimer's disease, are characterized by progressive accumulation of hyperphosphorylated and pathologic tau protein in association with onset of cognitive and behavioral impairment. Tau pathology is also associated with increased susceptibility to seizures and epilepsy, with tau−/− mice showing seizure resistance in some epilepsy models. To better understand how tau pathology is related to neuronal excitability, we performed whole-cell patch-clamp electrophysiology in dentate gyrus granule cells of tau−/− and human-tau expressing, htau mice. The htau mouse is unique from other transgenic tau models in that the endogenous murine tau gene has been and replaced with readily phosphorylated human tau. We assessed several measures of neuronal excitability, including evoked action potential frequency and excitatory synaptic responses in dentate granule cells from tau−/−, htau, and non-transgenic control mice at 1.5, 4, and 9 months of age. Compared to age matched controls, dentate granule cells from both tau−/− and htau mice had a lower peak frequency of evoked action potentials and greater paired pulse facilitation, suggesting reduced neuronal excitability. Our results suggest that neuronal excitability is more strongly influenced by the absence of functional tau than by the presence of pathologic tau. These results also suggest that tau's effect on neuronal excitability is more complex than previously understood.
AB - Tauopathies, including Alzheimer's disease, are characterized by progressive accumulation of hyperphosphorylated and pathologic tau protein in association with onset of cognitive and behavioral impairment. Tau pathology is also associated with increased susceptibility to seizures and epilepsy, with tau−/− mice showing seizure resistance in some epilepsy models. To better understand how tau pathology is related to neuronal excitability, we performed whole-cell patch-clamp electrophysiology in dentate gyrus granule cells of tau−/− and human-tau expressing, htau mice. The htau mouse is unique from other transgenic tau models in that the endogenous murine tau gene has been and replaced with readily phosphorylated human tau. We assessed several measures of neuronal excitability, including evoked action potential frequency and excitatory synaptic responses in dentate granule cells from tau−/−, htau, and non-transgenic control mice at 1.5, 4, and 9 months of age. Compared to age matched controls, dentate granule cells from both tau−/− and htau mice had a lower peak frequency of evoked action potentials and greater paired pulse facilitation, suggesting reduced neuronal excitability. Our results suggest that neuronal excitability is more strongly influenced by the absence of functional tau than by the presence of pathologic tau. These results also suggest that tau's effect on neuronal excitability is more complex than previously understood.
KW - Dentate granule cell
KW - EPSC
KW - Hippocampus
KW - Microtubule associated protein tau
KW - Tau
KW - Tauopathy
KW - htau
UR - http://www.scopus.com/inward/record.url?scp=85106568865&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85106568865&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2021.113766
DO - 10.1016/j.expneurol.2021.113766
M3 - Article
C2 - 34029610
AN - SCOPUS:85106568865
SN - 0014-4886
VL - 343
JO - Experimental Neurology
JF - Experimental Neurology
M1 - 113766
ER -