The transcription factor SP4 is reduced in postmortem cerebellum of bipolar disorder subjects: control by depolarization and lithium.
OBJECTIVE
Regulation of gene expression is important for the development and function of the nervous system. However, the transcriptional programs altered in psychiatric diseases are not completely characterized. Human gene association studies and analysis of mutant mice suggest that the transcription factor specificity protein 4 (SP4) may be implicated in the pathophysiology of psychiatric diseases. We hypothesized that SP4 levels may be altered in the brain of bipolar disorder (BD) subjects and regulated by neuronal activity and drug treatment.


METHODS
We analyzed messenger RNA (mRNA) and protein levels of SP4 and SP1 in the postmortem prefrontal cortex and cerebellum of BD subjects (n = 10) and controls (n = 10). We also examined regulation of SP4 mRNA and protein levels by neuronal activity and lithium in rat cerebellar granule neurons.


RESULTS
We report a reduction of SP4 and SP1 proteins, but not mRNA levels, in the cerebellum of BD subjects. SP4 protein and mRNA levels were also reduced in the prefrontal cortex. Moreover, we found in rat cerebellar granule neurons that under non-depolarizing conditions SP4, but not SP1, was polyubiquitinated and degraded by the proteasome while lithium stabilized SP4 protein.


CONCLUSIONS
Our study provides the first evidence of altered SP4 protein in the cerebellum and prefrontal cortex in BD subjects supporting a possible role of transcription factor SP4 in the pathogenesis of the disease. In addition, our finding that SP4 stability is regulated by depolarization and lithium provides a pathway through which neuronal activity and lithium could control gene expression suggesting that normalization of SP4 levels could contribute to treatment of affective disorders.
Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
Raquel
R
Pinacho
Nuria
N
Villalmanzo
Jasmin
J
Lalonde
Josep Maria
JM
Haro
J Javier
JJ
Meana
Grace
G
Gill
Belén
B
Ramos
D000328:Adult; D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D018692:Antimanic Agents / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000473:pathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009553:Nimodipine / Q000494:pharmacology; D011180:Postmortem Changes; D011189:Potassium Chloride / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D051706:Sp4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric
D018692:Antimanic Agents; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C497124:SP4 protein, human; D016329:Sp1 Transcription Factor; D051706:Sp4 Transcription Factor; D009553:Nimodipine; D011189:Potassium Chloride; D018021:Lithium Chloride