نجات از اختلال افسردگی فاز آخر طولانی مدت در یک مدل موش تراریخته تائو

Cognitive decline, the hallmark of Alzheimer's disease, and accompanying neuropsychiatric symptoms share dysfunctions of synaptic processes as a common cellular pathomechanism. Long-term potentiation has proven to be a sensitive tool for the “diagnosis” of such synaptic dysfunctions. Much less, however, is known about how long-term depression (LTD), an alternative mechanism for the storage of memory, is affected by Alzheimer's disease progression. Here, we demonstrate that impaired late LTD (>3 hours) in THY-Tau22 mice can be rescued by either inhibition of glycogen synthase kinase-3 (GSK3β) activity or by application of the protein-phosphatase 2A agonist selenate. In line with these findings, we observed increased phosphorylation of GSK3β at Y216 and reduced total phosphatase activity in biochemical assays of hippocampal tissue of THY-Tau22 mice. Interestingly, LTD induction and pharmacologic inhibition of GSK3β appeared to downregulate GSK3ß activity via a marked upregulation of phosphorylation at the inhibitory Ser9 residue. Our results point to alterations in phosphorylation and/or dephosphorylation homeostasis as key mechanisms underlying the deficits in LTD and hippocampus-dependent learning found in THY-Tau22 mice.

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 and 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 and 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 and 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 and 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 and 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 and 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 and 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 and 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 and Van der Jeugd et al., 2011). LTD is dependent on activation of glycogen synthase kinase-3 (GSK3β) (Peineau et al., 2007 and 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 and Van der Jeugd et al., 2012). In tauopathies, active GSK3β is closely associated with neurofibrillary tangles (NFTs) (Kremer et al., 2011 and 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 and 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 and 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.

n 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 tau (Burnouf et al., 2012 and Van der Jeugd et al., 2011). This led us to conclude that LTD is sensitive to subtle subcellular and/or molecular changes that either accompany or are caused by tau hyperphosphorylation, a hypothesis which was tested in the present study. We previously documented in corollary studies with C57/Bl6 control mice of comparable age that this type of L-LTD depends on activation of the NMDAR subtype of glutamate receptors (Ahmed et al., 2011). Therefore, we first tested here whether the observed LTD deficit in THY-Tau22 mice could be because of a change in NMDAR-dependent induction mechanisms. Although bath application of the broad-spectrum NMDAR antagonist D-AP5 (100 μM, see Ahmed et al., 2011) to WT slices resulted in an inhibition of the robust L-LTD (vehicle: 52 minutes: 43.9% ± 8.3%, 240 minutes: 69.6% ± 6.9%, n = 8; D-AP5 (52 minutes: 82.5% ± 8.1%, 240 minutes: 97.4% ± 10.8%, n = 7); Fig. 1A), the compound had no discernible effect in THY-Tau22 mice where LTD was already markedly diminished compared with WT mice (Fig. 1B). To exclude the possibility that the LTD was dependent on L-type VGCC as reported in aged rats (Foster, 2007), nifedipine was tested. As depicted in Fig. 1, bath application of nifedipine (10 μM) had no effect on LTD in both genotypes (WT Nifed. L-LTD: 52 minutes: 51.1% ± 9.7%, n = 7, Fig. 1A; THY-Tau22 Nifed: 76.3% ± 7.0%, n = 7; Fig. 1B). Full-size image (61 K) Fig. 1. Blockade of NMDAR and L-type voltage-gated calcium channels (VGCC) has no effect on LTD in THY-Tau22 mice. (A) Antagonism of NMDAR with 100 μM D-AP5 blocks L-LTD in WT controls (open circles), but blockade of L-type VCCC with nifedipine has no effect on L-LTD in WT controls (filled diamonds) when compared with vehicle controls (open squares). (B) Application of 100 μM D-AP5 (open circles) has no discernible effect on the deficient LTD in THY-Tau22 mice. Antagonism of L-type VCCC with nifedipine does not affect L-LTD in THY-Tau22 mice (filled diamonds) when compared with THY-Tau22 mice that received vehicle alone (open squares). In all studies, the open box indicates the duration of drug application and the filled boxes the time schedule of low-frequency trains. Insets show representative analog traces for the 3 conditions tested. Traces were recorded at the time points indicated by numbers in the figures. Abbreviations: LTD, long-term depression; L-LTD, late LTD; WT, wild type.