Removal of FKBP12 Enhances mTOR-Raptor Interactions, LTP, Memory, and Perseverative/Repetitive Behavior

Abstract

SUMMARY FK506 binding protein 12 (FKBP12) binds the immunosuppressant drugs FK506 and rapamycin and regulates several signaling pathways, including mammalian target of rapamycin (mTOR) signaling. We determined whether the brain-specific disruption of the FKBP12 gene altered mTOR signaling, synaptic plasticity, and memory. Biochemically, the FKBP12-deficient mice displayed increases in basal mTOR phosphorylation, mTOR-Raptor interactions, and p70 S6 kinase (S6K) phosphorylation. Electrophysiological experiments revealed that FKBP12 deficiency was associated with an enhancement in long-lasting hippocampal long-term potentiation (LTP). The LTP enhancement was resistant to rapamycin, but not anisomycin, suggesting that altered translation control is involved in the enhanced synaptic plasticity. Behaviorally, FKBP12 conditional knockout (cKO) mice displayed enhanced contextual fear memory, and autistic/obsessive-compulsive-like perseveration in several assays including the water maze, Y-maze reversal task, and the novel object recognition task. Our results indicate that FKBP12 plays a critical role in the regulation of mTOR-Raptor interactions, LTP, memory, and perseverative behaviors.

Mouse model of Timothy syndrome recapitulates triad of autistic traits

“…findings from various anxiety tests, supports the notion that TS2-neo mice exhibit increased fear memory but no overt anxiety. Another gene-induced mouse model of ASD, the FKBP12-deficient mouse, shows normal anxiety but enhanced fear memory for context (but not tone) (8), whereas the valproic acid-induced rat model shows increased anxiety along with enhanced tone and context fear memory (14). Taken together, the behavior in various rodent models, including TS2-neo mice, is reminiscent of abnormal fear (14) and persistent memories (13) in humans.…”

“…4A). Increased marble burying is thought to be an index for repetitive/ perseverative behavior and compulsion, as supported by animal models of ASD and experiments with serotonin reuptake inhibitors used to treat the condition (7,8). Marble burying is also inhibited by calcium channel antagonists (9).…”

“…A new cohort of mice was tested in a water Y-maze, a test that called for a simple left/right decision (8) (Fig. 4C).…”

Notch signaling in the brain: In good and bad times

“…This pathway is essential in memory formation (Bekinschtein et al, 2007) and consolidation (Hoeffer et al, 2008). An interesting parallel between Notch and mTOR function can be found in the common LTD deficiency observed in hippocampal slices treated with PI3K-AktmTOR inhibitors (Hou and Klann, 2004) and the Notch1cKOs (Alberi et al, 2011).…”

Narrowing in on neurogenesis

“…[1][2][3][4] Two of the papers show that inhibiting glycogen synthase kinase 3β (GSK3β) increases neurogenesis and could potentially be a strategy for treating schizophrenia and Alzheimer's disease. The second pair of papers suggests that inhibiting mammalian target of rapamycin (mTOR; FRAP; RAFT1) can decrease neurogenesis and thus potentially offer a therapeutic strategy for epilepsy and obsessivecompulsive disorder (OCD).…”