TY - JOUR
T1 - Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease
AU - Hijazi, Sara
AU - Heistek, Tim S.
AU - Scheltens, Philip
AU - Neumann, Ulf
AU - Shimshek, Derya R.
AU - Mansvelder, Huibert D.
AU - Smit, August B.
AU - van Kesteren, Ronald E.
PY - 2020/12
Y1 - 2020/12
N2 - Neuronal network dysfunction is increasingly recognized as an early symptom in Alzheimer’s disease (AD) and may provide new entry points for diagnosis and intervention. Here, we show that amyloid-beta-induced hyperexcitability of hippocampal inhibitory parvalbumin (PV) interneurons importantly contributes to neuronal network dysfunction and memory impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We demonstrate that hippocampal PV interneurons become hyperexcitable at ~16 weeks of age, when no changes are observed yet in the intrinsic properties of pyramidal cells. This hyperexcitable state of PV interneurons coincides with increased inhibitory transmission onto hippocampal pyramidal neurons and deficits in spatial learning and memory. We show that treatment aimed at preventing PV interneurons from becoming hyperexcitable is sufficient to restore PV interneuron properties to wild-type levels, reduce inhibitory input onto pyramidal cells, and rescue memory deficits in APP/PS1 mice. Importantly, we demonstrate that early intervention aimed at restoring PV interneuron activity has long-term beneficial effects on memory and hippocampal network activity, and reduces amyloid plaque deposition, a hallmark of AD pathology. Taken together, these findings suggest that early treatment of PV interneuron hyperactivity might be clinically relevant in preventing memory decline and delaying AD progression.
AB - Neuronal network dysfunction is increasingly recognized as an early symptom in Alzheimer’s disease (AD) and may provide new entry points for diagnosis and intervention. Here, we show that amyloid-beta-induced hyperexcitability of hippocampal inhibitory parvalbumin (PV) interneurons importantly contributes to neuronal network dysfunction and memory impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We demonstrate that hippocampal PV interneurons become hyperexcitable at ~16 weeks of age, when no changes are observed yet in the intrinsic properties of pyramidal cells. This hyperexcitable state of PV interneurons coincides with increased inhibitory transmission onto hippocampal pyramidal neurons and deficits in spatial learning and memory. We show that treatment aimed at preventing PV interneurons from becoming hyperexcitable is sufficient to restore PV interneuron properties to wild-type levels, reduce inhibitory input onto pyramidal cells, and rescue memory deficits in APP/PS1 mice. Importantly, we demonstrate that early intervention aimed at restoring PV interneuron activity has long-term beneficial effects on memory and hippocampal network activity, and reduces amyloid plaque deposition, a hallmark of AD pathology. Taken together, these findings suggest that early treatment of PV interneuron hyperactivity might be clinically relevant in preventing memory decline and delaying AD progression.
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UR - http://www.scopus.com/inward/citedby.url?scp=85071261025&partnerID=8YFLogxK
U2 - 10.1038/s41380-019-0483-4
DO - 10.1038/s41380-019-0483-4
M3 - Article
C2 - 31431685
AN - SCOPUS:85071261025
SN - 1359-4184
VL - 25
SP - 3380
EP - 3398
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 12
ER -