Effects of fingolimod administration in a genetic model of cognitive deficits

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Despite their distinction in modern psychiatry, cognitive disabilities in neuropsychiatric and neurodevelopmental disorders share commonalities in phenomenology (Couture et al., 2011) and pathophysiology (Pinkham et al., 2008). Impairments in information processing, particularly social information processing, are some of the most commonly noted deficits shared by neurodevelopmental and neuropsychiatric disorders (Sugranyes et al., 2011). Despite the relevance of cognitive disabilities, there are few therapeutic options to treat them. With the increasing recognition that severity of cognitive disabilities may have the greatest impact on the long‐term outcome of neuropsychiatric and neurodevelopmental patients, there is a requirement to develop treatments to improve cognitive function.
A potential therapeutic target, the prefrontal cortex (PFC), is a highly interconnected structure involved with top–down processing of sensorimotor information, and integration of this information affords complex cognitive functions (Miller, 2000; Fuster, 2001). Neuronal microcircuits within the PFC have essential roles in encoding, processing, and maintaining working memory (Goldman‐Rakic, 1995; Miller, 2000). PFC neurons show increased activity during memory maintenance, and this memory‐related activity has been attributed to glutamate‐dependent recurrent excitation within local circuits (Compte et al., 2000). Compromised glutamate release may diminish the ability of cortical circuits to maintain recurrent excitation and may cause failure during information maintenance mechanisms.
Several susceptibility genes associated with deficits in cognition have been targeted as contributing factors in symptom pathogenesis (Modinos et al., 2013). DTNBP1 encodes dystrobrevin‐binding protein 1 (dysbindin‐1) and is located in the “vulnerability locus” on chromosome 6p24‐22 (Straub et al., 1995). Spread across many diverse populations, genome‐wide association studies and family‐based pedigree studies have made genetic correlations between the DTNBP1 gene and the etiology of schizophrenia (Straub et al., 2002). Although variants of the DTNBP1 gene cannot be linked to every case of schizophrenia, there is evidence that negative and cognitive deficits may be attributed to diminished expression of the dysbindin‐1 protein (DeRosse et al., 2006; Donohoe et al., 2007).
Dysbindin‐1 is part of the biogenesis of lysosome‐related organelle complex 1 (BLOC‐1; Starcevic and Dell'Angelica, 2004). This complex is involved in multiple cellular functions, including synaptic vesicle dynamics (Larimore et al., 2011; Mullin et al., 2011). At the presynaptic level, its deficiency affects synaptic homeostasis, synaptic vesicle composition, and vesicle fusion (Ji et al., 2009; Newell‐Litwa et al., 2009). Previously, using dysbindin‐1 deficient mice (henceforth, dysbindin‐1 mice), we found decreases in the replenishment of the readily releasable pool of synaptic glutamate vesicles in the PFC, decreases in quantal size and probability of glutamate release, deficits in the rate of endo‐ and exocytosis, and deficits in memory and working memory tasks (Jentsch et al., 2009; Karlsgodt et al., 2011; Glen et al., 2014; Saggu et al., 2013). Here, we hypothesize that restoring glutamate levels in the PFC may alleviate some of the cognitive deficits exhibited by dysbindin‐1 mice. To increase endogenous levels of glutamate, we use a novel drug, fingolimod.
Fingolimod (Gilenya; FTY720) is active as fingolimod phosphate (Groves et al., 2013; Martin and Sospreda, 2014). It has been shown that fingolimod selectively increases endogenous levels of brain‐derived neurotrophic factor (BDNF; Deogracias et al., 2012). Evidence supporting a role for BDNF in synaptic transmission and neuronal excitability is strong (Pozzo‐Miller et al., 1999; Tyler and Pozzo‐Miller 2001, 2003; Chapleu et al., 2009). Activation of tropomyosin receptor kinase B (TrkB) receptors by BDNF induces new protein synthesis (Halegoua et al., 1991; Lewin and Barde, 1996), and Tyler and Pozzo‐Miller (2001) have shown that BDNF increases release probability and the number of docked glutamate vesicles in the hippocampus. Furthermore, evidence indicates a link between dysbindin and BDNF.
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