Abstract
Identifying genetic factors that modify an individual's susceptibility to cognitive decline in aging is critical to understanding biological processes involved and mitigating risk associated with a number of age‐related disorders. Recently, heterochromatin protein 1 binding protein 3 (Hp1bp3) was identified as a mediator of cognitive aging. Here, we provide a mechanistic explanation for these findings and show that targeted knockdown of Hp1bp3 in the hippocampus by 50%–75% is sufficient to induce cognitive deficits and transcriptional changes reminiscent of those observed in aging and Alzheimer's disease brains. Specifically, neuroinflammatory‐related pathways become activated following Hp1bp3 knockdown in combination with a robust decrease in genes involved in synaptic activity and neuronal function. To test the hypothesis that Hp1bp3 mediates susceptibility to cognitive deficits via a role in neuronal excitability, we performed slice electrophysiology demonstrate transcriptional changes after Hp1bp3 knockdown manifest functionally as a reduction in hippocampal neuronal intrinsic excitability and synaptic plasticity. In addition, as Hp1bp3 is a known mediator of miRNA biogenesis, here we profile the miRNA transcriptome and identify mir‐223 as a putative regulator of a portion of observed mRNA changes, particularly those that are inflammatory‐related. In summary, work here identifies Hp1bp3 as a critical mediator of aging‐related changes at the phenotypic, cellular, and molecular level and will help inform the development of therapeutics designed to target either Hp1bp3 or its downstream effectors in order to promote cognitive longevity.
Highlights
Most individuals will experience some degree of cognitive decline during aging, the extent of this decline can vary widely
While we demonstrate here Theta‐burst stimulation (TBS) is capable of inducing long‐term potentiation (LTP) in both strains, other types of LTP have been shown to be reduced in the D2 strain (Schimanski & Nguyen, 2005), which may explain their poor performance on contextual fear conditioning—a task which requires synaptic plasticity (Tang et al, 1999)
Our data support a critical role for heterochromatin protein 1 binding protein 3 (Hp1bp3) in modifying cognition and neuronal function, as well as the transcriptional programs underlying both
Summary
Most individuals will experience some degree of cognitive decline during aging, the extent of this decline can vary widely. Plasma membrane ion channels and receptors are critical regulators of neuronal excitability and synaptic plasticity, leading candidate mechanisms for memory storage (Kandel, 2001) Taken together, this information led us to hypothesize that Hp1bp may be mediating its effects on cognitive longevity via the modulation of hippocampal neuronal excitability. We assess the effects of a hippocampus‐specific knockdown (KD) of Hp1bp on cognitive function, the hippocampal transcriptome, neuronal excitability, and synaptic plasticity We perform these experiments in both the C57BL6/J (B6) and D2 inbred mouse strains to enhance the rigor of our approach, as recent findings suggest studies conducted in a single genetic background limit the generalizability of mouse studies (Sittig et al, 2016). It was our hypothesis that any effect of Hp1bp KD observed across strains would be robust and potentially translatable to diverse genetic contexts
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