Wojcik, S.M. (S.M.)

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    Enhanced anxiety, depressive-like behaviour and impaired recognition memory in mice with reduced expression of the vesicular glutamate transporter 1 (VGLUT1)
    (Wiley Blackwell, 2007) Elizalde, N. (N.); Wojcik, S.M. (S.M.); Totterdell, S. (S.); Brose, N. (N.); Lasheras, B. (Berta); Rio, J. (Joaquín) del; Tordera, R.M. (Rosa María)
    Three isoforms of a vesicular glutamate transporter (VGLUT1-3) have been identified. Of these, VGLUT1 is the major isoform of the cerebral cortex and hippocampus where it is selectively located on synaptic vesicles of excitatory glutamatergic terminals. Variations in VGLUT1 expression levels have a major impact on the efficacy of glutamate synaptic transmission. Given evidence linking alterations in glutamate neurotransmission to various neuropsychiatric disorders, we investigated the possible influence of a down-regulation of VGLUT1 transporter on anxiety, depressive-like behaviour and learning. The behavioural phenotype of VGLUT1 heterozygous mice (C57BL/6) was compared to WT littermates. Moreover, VGLUT1-3 expression, hippocampal excitatory terminal ultrastructure and neurochemical phenotype were analysed. VGLUT1 heterozygous mice displayed normal spontaneous locomotor activity, increased anxiety in the light-dark exploration test and depressive-like behaviour in the forced swimming test: no differences were shown in the elevated plus-maze model of anxiety. In the novel object recognition test, VGLUT1+/- mice showed normal short-term but impaired long-term memory. Spatial memory in the Morris water maze was unaffected. Western blot analysis confirmed that VGLUT1 heterozygotes expressed half the amount of transporter compared to WT. In addition, a reduction of the reserve pool of synaptic vesicles of hippocampal excitatory terminals and a 35-45 % reduction of GABA in the frontal cortex and the hippocampus were observed in the mutant mice. These observations suggest that a VGLUT1-mediated presynaptic alteration of the glutamatergic synapses, in specific brain regions, leads to a behavioural phenotype resembling certain aspects of psychiatric and cognitive disorders.
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    Increased vulnerability to depressive-like behaviour of mice with decreased expression of VGLUT1
    (Elsevier, 2009) Elizalde, N. (N.); Garcia-Garcia, A.L. (A.L.); Wojcik, S.M. (S.M.); Ramirez, M.J. (María Javier); Harro, J. (J.); Venzala, E. (E.); Rio, J. (Joaquín) del; Tordera, R.M. (Rosa María); Matrov, D. (Denis)
    Background: Many studies have linked depression to an increase in the excitatory-inhibitory ratio in the forebrain. Presynaptic alterations in a shared pathway of the glutamate/GABA cycle may account for this imbalance. Recent evidence suggests that decreased vesicular glutamate transporter 1 (VGLUT1) levels in the forebrain affects the glutamate/GABA cycle and induces helpless behaviour. Here we studied decreased VGLUT1 as a potencial factor enhancing a depressive-like phenotype in an animal model. Methods: Glutamate and GABA synthesis as well as oxidative metabolism were studied in heterozygous mice for the vesicular glutamate transporter 1 (VGLUT1+/-) and WT. Subsequently, the regulation of neurotransmitter levels, proteins involved in the glutamate/GABA cycle and behaviour by both genotype and chronic mild stress (CMS) was studied. Finally, the effect of chronic imipramine on VGLUT1 control and CMS mice was also studied. Results: VGLUT1+/- mice showed increased neuronal synthesis of glutamate, decreased cortical and hippocampal GABA, VGLUT1 and EAAT1, as well as helplessness and anhedonia. CMS induced an increase of glutamate and a decrease of GABA, VGAT and GAD65 in both areas and led to upregulation EAAT1 in the hippocampus. Moreover, CMS induced anhedonia, helplessness, anxiety and impaired recognition memory. VGLUT1+/- CMS mice showed a combined phenotype (genotype plus stress) and specific alterations, such as an upregulation of VGLUT2 and hyperlocomotion. Moreover, an increased vulnerability to anhedonia and helplessness reversible by chronic imipramine was shown. Conclusions: These studies highlight a crucial role for decreased VGLUT1 in the forebrain as a biological mediator of increased vulnerability to chronic mild stress.