The Effects of Fingolimod Administration in Dysbindin-1 Null-Mutant Mice, a Genetic Model of Cognitive Deficits
Becker-Krail, Darius D
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Estimated to affect 1 % of the population worldwide, schizophrenia is a mainly heritable neuropsychiatric disorder characterized by a range of symptoms from hallucinations and delusions to social withdrawal and cognitive deficits. Schizophrenia related deficits in the social and memory domains may be associated with diminished expression of the dystrobrevin-binding protein-1 (dysbindin-1). The lab has previously shown that lacking dysbindin-1 reduces glutamate release in the prefrontal cortex (PFC) through decreases in the ready releasable pool of synaptic vesicles, decreased rates of exo- and endocytosis, and diminished expression of L- and N-type Ca2+ channels. Fingolimod (Gilenya®), a drug used to treat multiple sclerosis and Rett syndrome, is known to increase endogenous levels of brain derived neurotrophic factor (BDNF), and in turn, it has been shown that BDNF increases N-type Ca2+ channels. To explore a potential means of restoring glutamate release, and perhaps improving cognitive deficits, we investigate the effects of fingolimod using a dysbindin-1 null mutant mouse. The mice were divided into two groups: saline or fingolimod treatment (1 mg/kg, IP injection; 7 days). Social interactions and memory were assessed across three genotypes (WT, HET and MUT) using both the social choice and preference for social novelty tasks. For both groups, BDNF concentration was assessed in PFC homogenate using an ELISA, and levels of intracellular [Ca2+] were analyzed in a crude PFC synaptosome preparation using a Fluo-4 Ca2+ assay. Relative to WT mice, dysbindin-1 MUT mice demonstrated impairments in novel social interaction, deficits in memory as measured through preference for social novelty, and a lower presynaptic intracellular [Ca2+]pfc. However, fingolimod treated MUT mice show significantly improved social interaction with novel mice, significantly improved memory as measured through preference for social novelty, higher [BDNF]pfc, and an increase in presynaptic intracellular [Ca2+]pfc. These results show promise for counteracting social and cognitive deficits associated with schizophrenia, and may shed light on the possible role of dysbindin-1 in symptom pathogenesis.