Regular articleRescue of impaired late–phase long-term depression in a tau transgenic mouse model
Introduction
It is well known that aging and the progression of neurodegenerative diseases like Alzheimer's disease (AD) are characterized by the deterioration of cognitive functions, in particular of declarative forms of memory (Di et al., 2007, Glodzik et al., 2011, Hornberger and Piguet, 2012, McKhann et al., 1984, Nestor et al., 2006, Sydow et al., 2011, Van der Jeugd et al., 2011, Van der Jeugd et al., 2012). Less known is that in most AD patients and some AD mouse models, the decline in cognition is accompanied by neuropsychiatric symptoms at some stage of the disease (Alexander et al., 2011, Lyketsos et al., 2011, Price et al., 2012, Van Der Jeugd et al., 2013). Since cognitive decline and psychiatric symptoms are due to dysfunctions of synaptic processes (Hoover et al., 2010, Moechars et al., 1999, Rowan et al., 2003, Ting et al., 2007, Van Spronsen and Hoogenraad, 2010), it is tempting to use readouts of synaptic function as early markers for the onset of AD pathology.
It is widely believed that synaptic function bidirectionally adapts to the recent history of activation by plastic changes in synaptic transmission. A robust sustained increase in synaptic transmission is referred to as long-term potentiation (LTP) and a lasting decrease is referred to as long-term depression (LTD). Both LTP and LTD are considered as models for memory storage at the cellular level and can be artificially induced by certain protocols of electrical stimulation (see Bliss and Collingridge, 1993, Citri and Malenka, 2008, Collingridge et al., 2010 for further details).
Over the past decade, LTP has developed into a prime tool for the detection of synaptic deficits in AD mouse models. This is because it has been proven to be a sensitive indicator for early-onset pathology, and its mechanisms are well explored which facilitates causal conclusions (Hoover et al., 2010, Moechars et al., 1999, Rowan et al., 2003, Ting et al., 2007). Impairments of LTP in brain regions such as the hippocampus and neocortex were described to precede neurodegenerative changes that are typical for clinical AD (Hoover et al., 2010, Moechars et al., 1999, Rowan et al., 2003, Ting et al., 2007). Although LTP has been extensively studied in animal models of AD, LTD, the physiological counterpart of LTP, has been largely neglected although recent evidence indicates that LTD is crucial for some types of hippocampus-dependent learning (Brigman et al., 2010, Collingridge et al., 2010, Goh and Manahan-Vaughan, 2012, Kemp and Manahan-Vaughan, 2007, Morice et al., 2007, Zeng et al., 2001). Therefore, LTD as a complementary mechanism for memory storage is likely to be affected by the progression of neurodegenerative diseases, both in human subjects and in mouse models.
Most studies that documented LTD changes in AD animal models focused on amyloid beta (Aß)-related pathology, examined only early phases and reported almost unanimously a strengthening of LTD (Chakroborty et al., 2012, Chang et al., 2006, Cheng et al., 2009, Hsieh et al., 2006, Kim et al., 2001, Li et al., 2009, Shankar et al., 2008, Ting et al., 2007). Recently, we described for the first time an impairment of LTD in a tauopathy mouse model (THY-Tau22 mice) (Van der Jeugd et al., 2011), which was previously found to have normal LTP (Schindowski et al., 2006). The impairment pertained particularly to the late phase of depression and paralleled the progression of tauopathy and memory impairments (Belarbi et al., 2011, Van der Jeugd et al., 2011).
LTD is dependent on activation of glycogen synthase kinase-3 (GSK3β) (Peineau et al., 2007, Peineau et al., 2009) and regulated by serine and/or threonine phosphatases (Winder and Sweatt, 2001). Both modulate the phosphorylation state of the microtubule associated protein tau and tau hyperphosphorylation has been identified as one of the most critical molecular events in tauopathies and the progression of AD (Alonso et al., 2001, Braak et al., 1998, Brion et al., 1985, Buee et al., 2000, Mandelkow et al., 1995, Sergeant et al., 2008, Takashima, 2012, Van der Jeugd et al., 2012). In tauopathies, active GSK3β is closely associated with neurofibrillary tangles (NFTs) (Kremer et al., 2011, Leroy et al., 2007), and there is a concomitant reduction in total serine and/or threonine phosphatase activity (Sontag et al., 2004). These events might be instrumental in the development of tau pathology and subsequent memory impairments, because reducing GSK3β activity or promoting protein-phosphatase 2A (PP2A) activity were reported to be beneficial in tau mouse models (Bhat et al., 2004, Corcoran et al., 2010, van Eersel et al., 2010).
Here, we report the apparent paradox that inhibition of GSK3β deteriorates LTD under physiological control conditions but rescues an impaired late LTD (L-LTD) in THY-Tau22 mice. The LTD deficit in THY-Tau22 mice was also rescued by activation of the PP2A complex by selenate application (Corcoran et al., 2010, van Eersel et al., 2010). Thus, normalizing the phosphorylation and/or dephosphorylation imbalance in tau phosphorylation reinstates L-LTD, a functional marker that is susceptible to early synaptic deficits in tauopathies.
Section snippets
Animals
Male THY-Tau22 mice of C57/Bl6J background (10–12 month old) and littermate wild-type (WT) animals were generated by overexpression of human 4-repeat tau mutated at sites G272 V and P301 S under the control of Thy1.2 promoter (Schindowski et al., 2006). All animals were kept in standard animal cages under conventional laboratory conditions (12 hour/12 hour light-dark cycle, 22 °C), with ad libitum access to food and water. They were maintained and experiments were conducted in accordance with
L-LTD is NMDAR dependent and independent of L-type VGCC
In a recent study, we reported that 10- to 12-month-old THY-Tau22 mice displayed attenuated LTD in the hippocampal CA1-region in vitro, whereas the same induction protocol evoked robust late-phase LTD in WT littermates (Van der Jeugd et al., 2011). The CA1-LTD deficit in THY-Tau22 mice occurred at an age when no histochemical and biochemical signs of neuronal loss or neurodegeneration were noticeable in this region, in contrast to a prominent hyperphosphorylation and abnormal phosphorylation of
Discussion
Here, we describe the rescue of L-LTD in THY-Tau22 mice, a mouse model of tauopathy. Synaptic plasticity is now widely acknowledged to be a sensitive tool to detect early signs of AD and tauopathies, but this awareness is predominantly based on studies that examined different forms of LTP (Rowan et al., 2003, Seabrook and Rosahl, 1999). Impairments of LTP in brain regions such as the hippocampus and neocortex were described to precede neurodegenerative changes that are typical for clinical AD (
Disclosure statement
The authors declare no conflict of interest.
Acknowledgements
The project was supported by FWO-Vlaanderen (grant G.0327.08 to Detlef Balschun and Rudi D'Hooge), IDO Project 06/004 to Rudi D'Hooge and Detlef Balschun, and OT 06/23 to Detlef Balschun. Additional financial support was provided by Inserm, CNRS, IMPRT, Région Nord/Pas-de-Calais, FEDER, AIRMA, France Alzheimer, ANR (ANR-08-MNP-002 and JC ADONTAGE, ANR MALZ ADORATAU), and LECMA/AFI, European Community Programmes APOPIS (FP6 Contract LSHM-CT-2003–503330), MEMOSAD (FP7 Grant Agreement No. 2006121
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