This Week in The Journal

Boosting FKBP1b Levels Reverses Age-Related Cognitive Decline

John C. Gant, Kuey-Chu Chen, Inga Kadish, Eric M. Blalock, Olivier Thibault, et al.

Aging is normally accompanied by cognitive decline, particularly in spatial and recognition memory. This decline is thought to result from small changes in neuronal morphology and physiology, such as decreases in the size of dendritic spines and reduced neuronal excitability. These changes might stem from dysregulation of calcium homeostasis as a result of increased influx, increased release from intracellular stores, decreased buffering, and/or impaired extrusion (reviewed in Toescu and Verkhratsky, 2007, Aging Cell 6:267). One consequence of this dysregulation is greater activation of calcium-dependent K⁺ channels, resulting in larger slow afterhyperpolarizations (sAHPs) after spikes and reduced neuronal excitability.

sAHPs following spike bursts evoked by intracellular current injection (lower trace) were smaller in hippocampal slices from FKBP1b-supplemented old rats (red) than those in control old rats (turquoise). See Gant et al. for details.

One protein implicated in calcium dysregulation during aging is FK506 binding protein 1b (FKBP1b). Among other activities, FKBP1b inhibits opening of ryanodine receptors, which allow calcium release from internal stores. Previous studies by Gant and colleagues indicated that FKBP1b expression decreases in rats during aging and is abnormally low in Alzheimer's disease patients. Moreover, knocking down FKBP1b amplified calcium transients and sAHPs in hippocampal neurons of young rats.

These authors now provide additional evidence that reduction in FKBP1b contributes to age-associated cognitive decline. Increasing FKBP1b expression in rat hippocampus via viral infection fully rescued age-associated performance deficits on the Morris water maze. Whereas old control rats showed memory impairments compared to young rats, FKBP1b-supplemented old rats did not. In hippocampal slices from these same animals, sAHP amplitude and duration were similar in young and FKBP1b-supplemented old rats, but were larger in aged controls. Notably, the amount of impairment on the water maze was correlated with the amplitude and duration of sAHPs across individual rats. Experiments in slices confirmed that elevating FKBP1b expression reduced the amplitude of both spike-induced calcium transients and sAHPs in old rats.

These data support the hypothesis that age-associated decreases in FKBP1b expression contribute to cognitive decline by increasing spike-induced calcium transients. Although the results do not rule out the possibilities that reduced FKBP1b expression has calcium-independent effects on cognitive decline or that calcium dysregulation leads to cognitive decline through processes other than increasing the sAHP, they do support the idea that restoring FKBP1b to normal levels can reverse cognitive deficits in old age.

Atf3 and Other Genes Are Upregulated after TSC2 Knockdown

Duyu Nie, Zehua Chen, Darius Ebrahimi-Fakhari, Alessia Di Nardo, Kristina Julich, et al.

(see pages 10762–10772)

Tuberous sclerosis (TSC) is a disease characterized by the formation of benign tumors in multiple organs, including the brain. Nearly all people with TSC have epilepsy, ∼45% have intellectual disability, and up to 50% have autism, but the extent to which these conditions result from the presence of tumors in the brain is unclear. Indeed, it has been hypothesized that autistic and cognitive features may result from more subtle changes in neuronal development, synaptogenesis, synaptic plasticity, and/or myelination.

TSC is caused by mutations in TSC1 or TSC2. These genes encode proteins that work together to prevent activation of mTORC1, a major regulator of protein translation in response to environmental signals. Loss of TSC1 or TSC2 function leads to hyperactivation of mTORC1, and the resulting dysregulation of protein translation is thought to underlie most of the pathological features of TSC. Because several other monogenic disorders associated with autism and intellectual disability also affect mTORC1, identifying which mRNAs this complex regulates may provide insight into the molecular underpinnings of these conditions. With this goal, Nie et al. used the translating ribosome affinity purification (TRAP) technique to detect ribosome-associated mRNAs in rodent hippocampal neurons and to determine how knockdown of TSC2 altered the translational profile.

TSC2 knockdown caused downregulation of 17 genes and upregulation of 65. The upregulated genes included activating transcription factor-3 (Atf3), which is typically upregulated in response to neuronal stress. A downstream target of Atf3, the actin-severing protein gelsolin, was also upregulated. Not surprisingly, knocking down Atf3 prevented upregulation of gelsolin after TSC2 knockdown. More interestingly, knocking down Atf3 rescued spine density, which was reduced by TSC2 knockdown. Treatment with rapamycin, an mTORC1 inhibitor, prevented upregulation of Atf3, but it did not prevent upregulation of gelsolin or rescue spine density.

These results identify several genes that may be linked to the neurological features of TSC. But the inability of rapamycin to rescue some effects of TSC2 knockdown suggests that these particular effects are independent of mTORC1 activation. Clearly much more work will be required to understand how the numerous effects of TSC2 mutation coalesce to produce autism and intellectual disability.