Table 1.
Examples of genes regulated in the NAc by chronic social defeat stress and the effect of intra-NAc MS-275 and systemic fluoxetine
| Gene name | Social defeat | MS-275 | Fluoxetine | Gene product function and potential role in psychiatric diseases | Reference(s) |
|---|---|---|---|---|---|
| cort |  |
 a
|
|
Neuroprotective, decreases neuronal excitability; under circadian regulation (mediates sleep and motor activity) | Spier and de Lecea, 2000 |
| gja5 | |
a
|
⇔ | Rapidly transmits activity between adjacent neurons; decreased in NAc after cocaine self-administration | Bennett et al., 1999; Fricker and Miles, 2001 |
| dlgap1 | |
a
|
⇔ | Assembly of PSD complexes | Takeuchi et al., 1997 |
| kcne4 | |
|
⇔ | Prevents KCNQ1 (Kv1.1 and Kv1.3) potassium channel currents; attenuates presynaptic DA release | Grunnet et al., 2003 |
| adra1a | |
a
|
⇔ | Presynaptic noradrenergic autoreceptor; subsensitivity in clinical depression | Cedarbaum and Aghajanian, 1976 |
| grik2 | |
a
|
⇔ | Regulates early-phase EPSPs; pharmacological antagonism in NAc decreases performance for conditioned rewards | Watkins and Evans, 1981; Di Ciano et al., 2001 |
| slc17a7 | |
|
|
Glutamate transporter | Bellocchio et al., 2000 |
| rabep1 | |
a
|
⇔ | Tethers, docks, and fuses transport vesicles with organelles | Kawasaki et al., 2005 |
| rab3b | |
a
|
|
Located on synaptic vesicles and facilitates exocytosis by reducing Ca+ dependence | Schlüter et al., 2006 |
| tgfa | |
⇔a | |
Activates Erk, MAPK, JUN, STAT, P38, and Akt signaling | Ezeh and Farbman, 1998; Takeyama et al., 2000 |
| slit2 | |
a
|
|
Increases the branching of dendrites or axons; causes hyperpolarization of membrane potentials (opposite to BDNF) | Wang et al., 1999; Whitford et al., 2002; Nishiyama et al., 2008 |
| abl1 | |
a
|
|
Tyrosine kinase (DNA binding) that increases dendritic branching | Jones et al., 2004 |
| nrn1 | |
|
|
Stimulated by BDNF, or cellular activity, to promote dendritic arborization | Naeve et al., 1997 |
| tnfrsf1a | |
|
|
Positive regulation of the I-κB kinase/NF-κB cascade, and gene transcription (via RNA polymerase II promoter) | Chen and Goeddel, 2002 |
| sin3b | |
a
|
|
Transcriptional repressor that forms a complex with HDAC1 and HDAC2 | van Ingen et al., 2006 |
| rcor1 | |
a
|
⇔ | Transcriptional repressor that complexes with HDAC1, HDAC2, and LSD1 | Lakowski et al., 2006 |
The table lists some of the genes that were regulated in the NAc by chronic (10 d) social defeat stress and the influence of chronic intra-NAc infusion of MS-275 or of chronic systemic fluoxetine administration. Genes regulated in the same direction by MS-275 and fluoxetine could represent part of a common, shared mechanism of antidepressant action. Genes uniquely affected by MS-275 may be useful for identifying novel biochemical pathways that promote antidepressant effects. Each gene listed contributes to forms of cellular plasticity, as indicated in the table. Some genes have previously been observed to contribute to stress-related illnesses. Gene abbreviations: cort, Cortistatin; gja5, gap junction protein α 5; dlgap1, discs (large homolog-associated protein 1); kcne4, potassium voltage-gated channel; adra1a, adrenergic α 1A receptor; grik2, ionotropic glutamate receptor (kainate 2); slc17a7, solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter member 7); rabep1, rabaptin (RAB GTPase binding effector protein 1); rab3b, member RAS oncogene family; tgfa, transforming growth factor α; slit 2, slit homolog 2; abl1, c-abl oncogene 1 (receptor tyrosine kinase); nrn1, neuritin 1; tnfrsf1a, tumor necrosis factor receptor superfamily member 1A; sin3b, SIN3 homolog B (transcription regulator); rcor1, REST corepressor 1.
aDenotes randomly selected genes whose regulation by MS-275 after social stress was validated by qPCR on independent tissue samples.