Memory deficit is a common manifestation of age-related cognitive impairment, of which depression is a frequently occurring comorbidity. Previously, we developed a submissive (Sub) mouse line, validated as a model of depressive-like behavior. Using learning paradigms testing hippocampus-dependent spatial and nonspatial memory, we demonstrate here that Sub mice developed cognitive impairments at earlier age (3 months), compared with wild-type mice. Furthermore, acute hippocampal slices from Sub animals failed to display paired-pulse facilitation, whereas primed burst stimulation elicited significantly enhanced long-term potentiation in region CA1, relative to control mice. Changes in synaptic plasticity were accompanied by markedly reduced hippocampal messenger RNA expression of insulin-like growth factor and brain-derived neurotrophic factor. Finally, we identified markedly elevated protein levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 in the hippocampi of Sub mice, which was exacerbated with age. Taken together, the results point to a linkage between depressive-like behavior and the susceptibility to develop age-related cognitive impairment, potentially by hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor–mediated glutamatergic signaling.
Extension of the human life expectancy introduced myriad health care and social problems, particularly significantly increased occurrence of neurodegenerative disease (Bear et al., 2007). Specifically, deterioration of memory integrity may occur with differential severity during aging. Although most people will not have dementia, but will instead undergo “normal” aging, a significant part of the population will experience aging-related cognitive impairment associated with decline of episodic memory and intellectual ability (Backman et al., 2001). These signs are also the earliest marks of emerging Alzheimer's disease (AD) at the preclinical stage (Castellani et al., 2006). Cognitive impairment and depression are 2 common age-related syndromes, each of which presents in approximately a quarter of the elderly population (Bennett and Thomas, 2014, Enache et al., 2011, Marazziti et al., 2010 and Potter and Steffens, 2007). Although exclusion criteria render problematic the estimation of the comorbidity of depression and cognitive impairment (Huang et al., 2011, Korczyn and Halperin, 2009 and Weisenbach et al., 2012), several studies have established depression as a risk factor for cognitive impairment and the development of dementia with age (Gabryelewicz et al., 2007, Katon et al., 2010 and Panza et al., 2010). Moreover, the most recent studies convincingly demonstrated objectively measurable deficits in key cognitive functions in a large proportion of patients in the midst of a major depressive episode (Papakostas, 2014 and Trivedi and Greer, 2014); for review, see Marazziti et al. (2010). Thus, depressed mood may possess a causal role in the Submissive (Sub) mice's subsequent development of cognitive impairment with age.
Alterations in the hippocampal expression of neurotrophic factors (Duman and Monteggia, 2006 and Martinowich et al., 2007) and the associated changes in synaptic plasticity observed in depression (Marsden, 2013) are associated with the development of cognitive decline (Pittenger and Duman, 2007 and Wuwongse et al., 2010). Furthermore, age-related changes in hippocampal synaptic plasticity have been shown to correlate with altered patterns of glutamate neurotransmission (Barnes, 1979, Barnes and McNaughton, 1980, Barnes et al., 2000 and Gleichmann et al., 2011). Changes in expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit GluA1 associated with aging were suggested to lead to changes in synaptic plasticity (Kim et al., 2005) and may be associated with age-dependent cognitive impairment (Pagliusi et al., 1994). In addition, the implication of AMPAR current in age-related changes in memory formation was supported by the recovery of age-related cognitive decline in rats via treatment with an AMPAR modulator (Bloss et al., 2008). Furthermore, altered patterns of synaptic plasticity in the hippocampus seen previously in animal models of depression (Alfarez et al., 2003 and Pavlides et al., 2002) were reversed by treatment with clinical antidepressants (Holderbach et al., 2007 and Matsumoto et al., 2005). Thus, accumulating evidence hints that behavioral disturbances accompanying neurodegenerative and affective disorders may share common molecular mechanisms (Bertram and Tanzi, 2005 and Rodriguez and Verkhratsky, 2011).
Among the behaviors expressed in affective disorders are dominance and submissiveness (Johnson and Carver, 2012, Pearson et al., 2010 and Price and Sloman, 1984). It was suggested that mechanisms responsible for the expression of dominance and submissiveness contribute to the pathogenesis of affective disorders such as anxiety, bipolar mood disorder, and major depressive disorders (Moussaieff et al., 2012, Nesher et al., 2013 and Pinhasov et al., 2005a). We investigated the link between affective disorders and cognitive decline using mice displaying robust characteristics of dominance and submissiveness (Feder et al., 2010, Malatynska and Knapp, 2005, Malatynska et al., 2005 and Malatynska et al., 2007). These animals were developed using selective breeding according to their behavioral traits (Feder et al., 2010 and Nesher et al., 2013). Sub mice were previously validated as a preclinical model of depression using a range of behavioral and pharmacological approaches (Malatynska et al., 2007, Nesher et al., 2013 and Pinhasov et al., 2005a). In this study, we clearly demonstrate that the Sub mouse model of depressive behavior exhibits significant cognitive deterioration, which appears at early age (3 months) with altered hippocampal expression of the AMPAR subunit GluA1 and significant changes in synaptic plasticity.
Aging-associated memory impairment is linked to deterioration of hippocampal function (Rosenzweig and Barnes, 2003 and Wilson et al., 2006). This deterioration was reflected in the impairment of spatial memory–related tasks, either without (Hauser et al., 2009 and Shukitt-Hale et al., 2004) or with significant disruption of their performance in nonspatial paradigms (Banuelos et al., 2014, Beas et al., 2013, Burke et al., 2010, Gamiz and Gallo, 2012 and Roesch et al., 2012). The RAM paradigm is a standard hippocampus-dependent spatial memory task (Hodges, 1996). Hence, to study the wider impact of a depressive-like phenotype on aging-associated spatial memory impairment, we tested Dom, Sub, and wt animals in the RAM paradigm.
