The study by Liu et al., which describes the contribution of "leaky" type 2 ryanodine receptor (RyR2) calcium channels to memory impairments resulting from stress, comes at an exciting time for revisiting the role of RyR-evoked calcium dysregulation in behavioral and memory disorders. The authors describe a mechanism by which neuronal RyR2 channels have increased channel activity due to reduction in calstabin2 binding resulting from upregulation of stress signaling pathways. The presence of calstabin2 (which is in the FK binding protein 1 family) stabilizes RyR channel conformation so as to prevent excess calcium release. Likewise, calstabin2 removal results in increased channel sensitivity and excess calcium release. Through a series of biochemistry, neurophysiology, and behavioral assays, the study concludes that neuronal RyR2 remodeling underlies the cognitive dysfunction induced by stress, and therefore compounds such as S107, which stabilize the RyR2-calstabin2 interaction, may have potential for treating stress disorders.

The association between RyRs (and RyR2, in...  Read more

The study by Liu et al., which describes the contribution of "leaky" type 2 ryanodine receptor (RyR2) calcium channels to memory impairments resulting from stress, comes at an exciting time for revisiting the role of RyR-evoked calcium dysregulation in behavioral and memory disorders. The authors describe a mechanism by which neuronal RyR2 channels have increased channel activity due to reduction in calstabin2 binding resulting from upregulation of stress signaling pathways. The presence of calstabin2 (which is in the FK binding protein 1 family) stabilizes RyR channel conformation so as to prevent excess calcium release. Likewise, calstabin2 removal results in increased channel sensitivity and excess calcium release. Through a series of biochemistry, neurophysiology, and behavioral assays, the study concludes that neuronal RyR2 remodeling underlies the cognitive dysfunction induced by stress, and therefore compounds such as S107, which stabilize the RyR2-calstabin2 interaction, may have potential for treating stress disorders.

The association between RyRs (and RyR2, in particular) and synaptic plasticity/cognitive function has been approached before, and RyR dysfunction is increasingly implicated in memory disorders such as AD (Chakroborty and Stutzmann, 2011). The RyR2 stabilizing method used by Liu et al. may therefore hold promise in AD and other dementias in which the RyR2 is thought to be involved. This comes against a backdrop of recent disappointing clinical trials targeting β amyloid clearance (e.g., see ARF related news story). In these, and related studies, amyloid biomarkers were successfully reduced, but positive effects on cognitive performance in mild to moderate AD patients were absent. While the argument that drug treatment was initiated too late in the disease process may be valid, one might still expect to see trends toward improvement in treated patients. Rather, the emerging trend in the related 10+ clinical trials is towards patient worsening under this approach. This is fueling increasing skepticism that β amyloid is the relevant target, and highlights the need for alternative therapeutic strategies to be pursued.

To this end, there is increasing evidence that RyR-targeted therapies would be an optimistic and productive approach, and studies such as that of Liu et al. provide critical pieces of mechanistic support for how and why such strategies would be effective. Complementary studies relevant to the AD field (such as Oulès et al., 2012; Peng et al., 2012; Chakroborty et al., 2010; and Stutzmann et al., 2006) all consistently report that treatment with RyR antagonists provides beneficial outcomes in a variety of parameters in AD mouse models—ranging from cellular physiology, intracellular calcium signaling, and antioxidant effects to behavioral assays and amyloid deposition. The Liu study also provides the important link to RyR2 dysregulation, as it is this isoform that is upregulated in early AD/MCI patients and in experimental AD models (Bruno et al., 2012; Oules et al., 2012; Chakroborty et al., 2009; Paula-Lima et al., 2011). Given the advances obtained by investigating therapeutic applications of RyR stabilizers in related neurological and psychiatric fields, hopefully these soon can be translated to neurodegenerative disease and dementias.

References:
Bruno AM, Huang JY, Bennett DA, Marr RA, Hastings ML, Stutzmann GE (2012) Altered ryanodine receptor expression in mild cognitive impairment and Alzheimer's disease. Neurobiology of Aging 33(5):1001.e1-6. Abstract

Chakroborty S, Goussakov I, Miller MB, Stutzmann GE (2009) Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3xTg-AD mice. J Neurosci 29:9458-70. Abstract

Chakroborty S, Briggs C, Goussakov I, Miller MB, Stutzmann GE (2010) Reversal of Early Calcium-Signaling Deficits in AD with Ryanodine Receptor Blockers: Normalization of ER Stores, Synaptic Plasticity and RyR expression. Society for Neuroscience abstract 748-20.

Chakroborty S, Stutzmann GE (2011) Early calcium dysregulation in Alzheimer's disease: setting the stage for synaptic dysfunction. Life Science, 54(8):752-62. Abstract

Oulès B, Del Prete D, Greco B, Zhang X, Lauritzen I, et al. (2012) Ryanodine Receptor Blockade Reduces Amyloid-β Load and Memory Impairments in Tg2576 Mouse Model of Alzheimer Disease. J Neurosci 32: 11820-34. Abstract

Paula-Lima AC, Adasme T, SanMartín C, Sebollela A, Hetz C, Carrasco MA, Ferreira ST, Hidalgo C. Amyloid β-peptide oligomers stimulate RyR-mediated Ca2+ release inducing mitochondrial fragmentation in hippocampal neurons and prevent RyR-mediated dendritic spine remodeling produced by BDNF. Antioxid Redox Signal. 2011;14(7):1209-23. Abstract

Peng J, Liang G, Inan S, Wu Z, Joseph DJ, et al. (2012) Dantrolene ameliorates cognitive decline and neuropathology in Alzheimer triple transgenic mice. Neurosci Lett 516: 274-9. Abstract

Stutzmann GE, Smith I, Caccamo A, Oddo S, LaFerla FM, Parker I (2006) Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult and aged Alzheimer’s disease mice. Journal of Neuroscience, 26(20) 5180-9. Abstract

Ziviani E, Lippi G, Bano D, Munarriz E, Guiducci S, Zoli M, Young KW, Nicotera P (2011) Ryanodine receptor-2 upregulation and nicotine-mediated plasticity. EMBO J 30:194-204. Abstract

View all comments by Grace (Beth) Stutzmann

My colleagues and I read with great interest this paper from the Marks group, showing that chronic stress can interfere with the interactions between FKBP12.6/1b (calstabin2) and ryanodine receptors (RyRs), thereby inducing Ca2+ leak from RyRs and cognitive dysfunction. This group pioneered the study of leaky RyRs in cardiac function and heart failure, and now extends its studies to stress and leaky RyRs in the hippocampus. This work is of particular interest to us because we published two papers last year showing that disrupting essentially the same FKBP1b-RyR interaction by specific knockdown of FKBP1b can recapitulate the Ca2+ dysregulation that characterizes hippocampal aging in rats (Gant et al., 2011), and that multiple RyR-stabilizing immunophilins and junctophilins are downregulated in the hippocampus of incipient Alzheimer’s disease subjects (Blalock et al., 2011). We have known for some time that excessive release of Ca2+ from RyRs is a major contributor to the Ca2+ dysregulation phenotype of aged rats (Gant et al., 2006; Thibault et al., 2007). That result, combined...  Read more

My colleagues and I read with great interest this paper from the Marks group, showing that chronic stress can interfere with the interactions between FKBP12.6/1b (calstabin2) and ryanodine receptors (RyRs), thereby inducing Ca2+ leak from RyRs and cognitive dysfunction. This group pioneered the study of leaky RyRs in cardiac function and heart failure, and now extends its studies to stress and leaky RyRs in the hippocampus. This work is of particular interest to us because we published two papers last year showing that disrupting essentially the same FKBP1b-RyR interaction by specific knockdown of FKBP1b can recapitulate the Ca2+ dysregulation that characterizes hippocampal aging in rats (Gant et al., 2011), and that multiple RyR-stabilizing immunophilins and junctophilins are downregulated in the hippocampus of incipient Alzheimer’s disease subjects (Blalock et al., 2011). We have known for some time that excessive release of Ca2+ from RyRs is a major contributor to the Ca2+ dysregulation phenotype of aged rats (Gant et al., 2006; Thibault et al., 2007). That result, combined with studies of rapamycin (which disrupts FKBPs) and our findings that FKBP1b gene expression declines in hippocampus with aging/AD, and clues from the cardiac studies of the Marks group, led us to directly manipulate FKBP1b expression in several recent studies. To date, our results are consistent with the hypothesis that declining function of FKBPs and other RyR-stabilizing molecules is responsible for hippocampal Ca2+ dysregulation, unhealthy cognitive aging, and, in part, early-stage AD.

This new paper by Liu and collaborators on stress and hippocampal dysregulation now provides an added perspective to the FKBP-RyR involvement in aging/AD. It shows that chronic stress can mimic the effects of aging on this mechanism. In turn, this fits well with our longstanding interest in the roles of glucocorticoids in brain aging and Ca2+ dysregulation (Kerr et al., 1989; Porter and Landfield, 1998), and suggests intriguing new directions for research on the interactions of glucocorticoids and aging in initiating AD.

References:
Gant JC, Chen KC, Norris CM, Kadish I, Thibault O, Blalock EM, Porter NM, Landfield PW. Disrupting function of FK506-binding protein 1b/12.6 induces the Ca²+-dysregulation aging phenotype in hippocampal neurons. J Neurosci. 2011 Feb 2;31(5):1693-703. Abstract

Blalock EM, Buechel HM, Popovic J, Geddes JW, Landfield PW. Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease. J Chem Neuroanat. 2011 Oct;42(2):118-26. Abstract

Gant JC, Sama MM, Landfield PW, Thibault O. Early and simultaneous emergence of multiple hippocampal biomarkers of aging is mediated by Ca2+-induced Ca2+ release. J Neurosci. 2006 Mar 29;26(13):3482-90. Abstract

Thibault O, Gant JC, Landfield PW. Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: minding the store. Aging Cell. 2007 Jun;6(3):307-17. Abstract

Kerr DS, Campbell LW, Hao SY, Landfield PW. Corticosteroid modulation of hippocampal potentials: increased effect with aging. Science. 1989 Sep 29;245(4925):1505-9. Abstract

Porter NM, Landfield PW. Stress hormones and brain aging: adding injury to insult? Nat Neurosci. 1998 May;1(1):3-4. Abstract

View all comments by Philip Landfield