Chronic fluoxetine treatment induces brain region-specific upregulation of genes associated with BDNF-induced long-term potentiation

Abstract

Several lines of evidence implicate BDNF in the pathogenesis of stress-induced depression and the delayed efficacy of antidepressant drugs. Antidepressant-induced upregulation of BDNF signaling is thought to promote adaptive neuronal plasticity through effects on gene expression, but the effector genes downstream of BDNF has not been identified. Local infusion of BDNF into the dentate gyrus induces a long-term potentiation (BDNF-LTP) of synaptic transmission that requires upregulation of the immediate early gene Arc. Recently, we identified five genes (neuritin, Narp, TIEG1, Carp, and Arl4d) that are coupregulated with Arc during BDNF-LTP. Here, we examined the expression of these genes in the dentate gyrus, hippocampus proper, and prefrontal cortex after antidepressant treatment. We show that chronic, but not acute, fluoxetine administration leads to upregulation of these BDNF-LTP-associated genes in a brain region-specific pattern. These findings link chronic effects of antidepressant treatment to molecular mechanisms underlying BDNF-induced synaptic plasticity.

Figure 1

Chronic fluoxetine administration leads to brain region-specific upregulation of LTP-associated genes. Changes in mRNA expression following fluoxetine treatment are expressed as fold change relative to the saline control group. (a) Prefrontal cortex, (b) hippocampus proper, (c) dentate gyrus. $N=7$ fluoxetine chronic, $n=8$ NaCl chronic, $n=5$ fluoxetine acute, $n=4$ NaCl acute (except neuritin chronic NaCl in DG, $n=7$). *$P<.05$, **$P<.01$, **$P<.001$ from Student's $t$-test.

Figure 2

Brain region-specific upregulation of BDNF exon-III specific mRNA in chronic fluoxetine-treated rats. (a) Prefrontal cortex, (b) hippocampus proper, (c) dentate gyrus. $N=7$ fluoxetine chronic, $n=8$ NaCl chronic, $n=5$ fluoxetine acute, $n=4$ NaCl acute. *$P<.05$, **$P<.01$ Student's $t$-test.