Chronic Fluoxetine Treatment Induces Brain Region-Specific Upregulation of Genes Associated with BDNF-Induced Long-Term Potentiation

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.

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BDNF and Control of Synaptic Plasticity in the Adult Brain

European Psychiatry ◽

10.1016/s0924-9338(09)70554-1 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1

Author(s):

C. Bramham

Keyword(s):

Synaptic Plasticity ◽

Dentate Gyrus ◽

Antidepressant Drugs ◽

Long Term Potentiation ◽

Memory Formation ◽

Adult Brain ◽

Early Gene ◽

Perforant Path ◽

Mammalian Brain

Experience-dependent changes in synaptic connectivity are thought to play a vital role not only in memory formation, but also in long-term adaptive responses involved in mood regulation, reward behavior, and pain control. The neurotrophin, brain-derived neurotrophic factor (BDNF), which has recently been implicated in memory formation and aspects of major depression, is also an important regulator of long-term synaptic plasticity in the adult mammalian brain. We have investigated BDNF function in the dentate gyrus, a brain region implicated in depression and the action of antidepressant drugs. Local infusion of BDNF into the dentate gyrus generated a long-term potentiation (LTP) of synaptic efficacy at medial perforant path-granule cell synapses. This LTP is associated with expression of the immediate early gene, Arc, in postsynaptic granule cells and transport of Arc mRNA to synaptic regions on dendrites. Using local infusion of antisense oligodeoxynucleotides to block Arc synthesis, we show that Arc is required for the induction and time-dependent consolidation of BDNF-induced LTP. The sustained synthesis of Arc during a critical time-window is required for local expansion of the actin cytoskeletal network in dendritic spines. These results identify Arc as a critical mediator of BDNF in long-term synaptic plasticity in the adult brain. Microarray expression profiling has further revealed a panel of genes that, like Arc, are strongly upregulated following acute BDNF infusion or chronic treatment with the antidepressant fluoxetine.

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Correlation between the induction of an immediate early gene,zif/268, and long-term potentiation in the dentate gyrus

Brain Research ◽

10.1016/0006-8993(92)90938-6 ◽

1992 ◽

Vol 580 (1-2) ◽

pp. 147-154 ◽

Cited By ~ 123

Author(s):

C.L. Richardson ◽

W.P. Tate ◽

S.E. Mason ◽

P.A. Lawlor ◽

M. Dragunow ◽

...

Keyword(s):

Dentate Gyrus ◽

Immediate Early Gene ◽

Long Term Potentiation ◽

Early Gene ◽

Immediate Early ◽

Term Potentiation

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Faculty Opinions recommendation of Novel environments enhance the induction and maintenance of long-term potentiation in the dentate gyrus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1020226.279662 ◽

2005 ◽

Author(s):

James Knierim

Keyword(s):

Dentate Gyrus ◽

Long Term Potentiation ◽

Term Potentiation ◽

Novel Environments

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Faculty Opinions recommendation of Novel environments enhance the induction and maintenance of long-term potentiation in the dentate gyrus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1020226.232447 ◽

2004 ◽

Author(s):

James L. McGaugh

Keyword(s):

Dentate Gyrus ◽

Long Term Potentiation ◽

Term Potentiation ◽

Novel Environments

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Spine formation pattern of new neurons is modulated by induction of long-term potentiation (LTP) in adult dentate gyrus

Neuroscience Research ◽

10.1016/j.neures.2009.09.321 ◽

2009 ◽

Vol 65 ◽

pp. S83

Author(s):

Noriaki Ohkawa ◽

Yoshito Saitoh ◽

Eri Tokunaga ◽

Toshio Kitamura ◽

Kaoru Inokuchi

Keyword(s):

Dentate Gyrus ◽

Long Term Potentiation ◽

Spine Formation ◽

Term Potentiation ◽

Formation Pattern

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Synaptic plasticity-dependent competition rule influences memory formation

Nature Communications ◽

10.1038/s41467-021-24269-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yire Jeong ◽

Hye-Yeon Cho ◽

Mujun Kim ◽

Jung-Pyo Oh ◽

Min Soo Kang ◽

...

Keyword(s):

Synaptic Plasticity ◽

Fear Conditioning ◽

Long Term Potentiation ◽

Memory Formation ◽

Specific Pattern ◽

Memory Encoding ◽

Competition Rule ◽

Term Potentiation ◽

Input Activity

AbstractMemory is supported by a specific collection of neurons distributed in broad brain areas, an engram. Despite recent advances in identifying an engram, how the engram is created during memory formation remains elusive. To explore the relation between a specific pattern of input activity and memory allocation, here we target a sparse subset of neurons in the auditory cortex and thalamus. The synaptic inputs from these neurons to the lateral amygdala (LA) are not potentiated by fear conditioning. Using an optogenetic priming stimulus, we manipulate these synapses to be potentiated by the learning. In this condition, fear memory is preferentially encoded in the manipulated cell ensembles. This change, however, is abolished with optical long-term depression (LTD) delivered shortly after training. Conversely, delivering optical long-term potentiation (LTP) alone shortly after fear conditioning is sufficient to induce the preferential memory encoding. These results suggest a synaptic plasticity-dependent competition rule underlying memory formation.

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