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AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity.

ABSTRACT: AKT is a kinase regulating numerous cellular processes in the brain, and mutations in AKT are known to affect brain function. AKT is indirectly implicated in synaptic plasticity, but its direct role has not been studied. Moreover, three highly related AKT isoforms are expressed in the brain, but their individual roles are poorly understood. We find in Mus musculus, each AKT isoform has a unique expression pattern in the hippocampus, with AKT1 and AKT3 primarily in neurons but displaying local differences, while AKT2 is in astrocytes. We also find isoform-specific roles for AKT in multiple paradigms of hippocampal synaptic plasticity in area CA1. AKT1, but not AKT2 or AKT3, is required for L-LTP through regulating activity-induced protein synthesis. Interestingly, AKT activity inhibits mGluR-LTD, with overlapping functions for AKT1 and AKT3. In summary, our studies identify distinct expression patterns and roles in synaptic plasticity for AKT isoforms in the hippocampus.

SUBMITTER: Levenga J

PROVIDER: S-EPMC5722612 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity.

Levenga Josien J Wong Helen H Milstead Ryan A RA Keller Bailey N BN LaPlante Lauren E LE Hoeffer Charles A CA

eLife 20171127

AKT is a kinase regulating numerous cellular processes in the brain, and mutations in <i>AKT</i> are known to affect brain function. AKT is indirectly implicated in synaptic plasticity, but its direct role has not been studied. Moreover, three highly related AKT isoforms are expressed in the brain, but their individual roles are poorly understood. We find in <i>Mus musculus</i>, each AKT isoform has a unique expression pattern in the hippocampus, with AKT1 and AKT3 primarily in neurons but displ ...[more]

PMID: 29173281

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Project description:The hippocampus is essential for learning and memory but also regulates emotional behavior. We previously identified the hippocampus as a major brain region that differs in rats bred for emotionality differences. Rats bred for low novelty response (LRs) exhibit high levels of anxiety- and depression-like behavior compared to high novelty responder (HR) rats. Manipulating the hippocampus of high-anxiety LR rats improves their behavior, although no work to date has examined possible HR/LR differences in hippocampal synaptic physiology. Thus, the current study examined hippocampal slice electrophysiology, dendritic spine density, and transcriptome profiling in HR/LR hippocampus, and compared performance on three hippocampus-dependent tasks: The Morris water maze, contextual fear conditioning, and active avoidance. Our physiology experiments revealed increased long-term potentiation (LTP) at CA3-CA1 synapses in HR versus LR hippocampus, and Golgi analysis found an increased number of dendritic spines in basal layer of CA1 pyramidal cells in HR versus LR rats. Transcriptome data revealed glutamate neurotransmission as the top functional pathway differing in the HR/LR hippocampus. Our behavioral experiments showed that HR/LR rats exhibit similar learning and memory capability in the Morris water maze, although the groups differed in fear-related tasks. LR rats displayed greater freezing behavior in the fear-conditioning task, and HR/LR rats adopted distinct behavioral strategies in the active avoidance task. In the active avoidance task, HRs avoided footshock stress by pressing a lever when presented with a warning cue; LR rats, on the other hand, waited until footshocks began before pressing the lever to stop them. Taken together, these findings concur with prior observations of HR rats generally exhibiting active stress coping behavior while LRs exhibit reactive coping. Overall, our current findings coupled with previous work suggest that HR/LR differences in stress reactivity and stress coping may derive, at least in part, from differences in the developing and adult hippocampus.

Dataset Information

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity.

Publications

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity.

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