title: Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Dheeraj S
authors.initials: DS
authors.lastname: Roy
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Autumn
authors.initials: A
authors.lastname: Arons
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Teryn I
authors.initials: TI
authors.lastname: Mitchell
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Pignatelli
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Tomás J
authors.initials: TJ
authors.lastname: Ryan
authors.affiliation: RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tonegawa
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D000647:Amnesia / Q000473:pathology / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D049229:Dendritic Spines / Q000473:pathology / Q000502:physiology; D018891:Dentate Gyrus / Q000166:cytology* / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D061345:Early Medical Intervention; D006801:Humans; D017774:Long-Term Potentiation; D008297:Male; D061212:Memory, Episodic; D057567:Memory, Long-Term / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D062308:Optogenetics; D058225:Plaque, Amyloid; D053764:Presenilin-1 / Q000235:genetics; D013569:Synapses / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D016875:tau Proteins / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; C054369:MAPT protein, human; D053764:Presenilin-1; D016875:tau Proteins