Specific Downregulation of Hippocampal ATF4 Reveals a Necessary Role in Synaptic Plasticity and Memory
Open accessAbstract
Prior studies suggested that the transcription factor ATF4 negatively regulates synaptic plastic and memory. By contrast, we provide evidence from direct in vitro and in vivo knockdown of ATF4 in rodent hippocampal neurons and from ATF4-null mice that implicate ATF4 as essential for normal synaptic plasticity and memory. In particular, hippocampal ATF4 downregulation produces deficits in long-term spatial memory and behavioral flexibility without affecting associative memory or anxiety-like behavior. ATF4 knockdown or loss also causes profound impairment of both long-term potentiation (LTP) and long-term depression (LTD) as well as decreased glutamatergic function. We conclude that ATF4 is a key regulator of the physiological state necessary for neuronal plasticity and memory.
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ATF4 is a transcription factor that enhances transcription of genes involved in compensation to ER stress and regulates expression of genes involved in plasticity, LTP, learning, and memory.
“ATF4 is a TF that both enhances the transcription of genes involved in compensation to ER stress and regulates the expression of genes involved in plasticity, LTP, learning, and memory.50”
From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [50]
The Introduction identifies ATF4 as a transcriptional regulator, and the Discussion and Results link it to hippocampal LTP, synaptic plasticity, and memory. But the passages do not say that ATF4 enhances transcription of genes that compensate for ER stress; they also establish its role in plasticity primarily through knockdown effects, rather than identifying a set of plasticity-related genes whose expression it regulates. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOthers highlight the role ATF4 can play as a transcriptional activator and enhancer of plasticity.
“others highlight the role ATF4 can play as a transcriptional activator and enhancer of plasticity.50”
From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [50]
The Introduction says ATF4 can act as a transcriptional activator, and the Discussion reports that ATF4 is required for normal synaptic plasticity. But the Discussion characterizes its role as permissive rather than a direct enhancement of plasticity, while the Results report no increase beyond control levels with ATF4 overexpression. The source therefore supports a positive role in plasticity, but not the stronger implication that ATF4 enhances it above normal levels. (LLM, conf=0.83)
Experimental — accuracy not yet measuredRelief of transcriptional repression owing to ATF4, a mammalian analogue of CREB2, seems to be important for the maintenance of hippocampal LTP.
“Similarly, relief of transcriptional repression owing to ATF4, a mammalian analogue of CREB2, seems to be important for the maintenance of hippocampal LTP102,103.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [103]
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- Authors
- Pasini, S., Corona, C., Liu, J., Greene, L. A., & Shelanski, M. L.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Shelanski, Michael L.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 11
- Issue
- 2
- Pages
- 183-191
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4822418
- OpenAlex
- W2020259580
- Cited by
- 116
- References
- 38
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 16 · 2023: 11 · 2022: 7 · 2021: 9 · 2020: 12 · 2019: 11 · 2018: 9 · 2017: 12 · 2016: 9 · 2015: 1
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (AG08702, P50AG008702)
- National Institute of Neurological Disorders and Stroke (P50-NS38370, P50NS038370)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- ATF4, transcription factors, hippocampal neurons, synaptic plasticity, memory, long-term potentiation, long-term depression, spatial memory, behavioral flexibility, glutamatergic function, anxiety-like behavior
- MeSH terms
- Animals, Hippocampus, Memory, Neuronal Plasticity, Neurons, Synapses, Mice, Knockout, Mice, Activating Transcription Factor 4
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