GENOMICS AND CELL

P. Laeng,

V. Charles, C.E. Drabik, A. Lemire, J.F. Russo, L. Jurata, Y. Bukhman, H. Yokoe,

Multiple

genetic and environmental factors appear to be responsible for the mood changes

and the wide spectrum of symptoms associated with bipolar disorder (BD).  The

influence of these factors on gene expression can be measured by a microarray

analysis of brain tissue from BD patients and normal controls.  The alteration

of genes in neuronal cells or brains from rodents exposed to mood stabilizing

drugs can add to the identification of molecular targets for therapeutic

Rats were

exposed to electroconvulsive seizures (ECS) to model electroconvulsive therapy (ECT),

the treatment of choice for medication-resistant BD.  ECS increased by 1.5 to

11-fold or decreased by at least 34% the expression of 135 unique genes in the

frontal cortex and hippocampus.  They included 90 genes not reported in prior

studies of ECS or seizure responses. RT-PCR confirmed 44 of 60 selected gene

changes.  Multiple genes were identified within distinct pathways, including the

BDNF/MAP kinase/cAMP/CREB pathway (15 genes), the arachidonic acid pathway (5

genes), immediate-early genes (10 genes), neurogenesis pathways (12 genes), and

exercise response genes (12 genes).  Neurogenesis, neurite outgrowth neuronal

plasticity, and cAMP/PKA signaling pathways may mediate the therapeutic effects

To

determine if some changes in the ECS  experiments can be reproduced with drugs

known to be effective in BD, mice were treated with 500mg/kg (i.p.) of Valproate

(VPA) for 24 hours.  221 and 194 genes changed in the hippocampus and frontal

cortex respectively (fold change >1.25, p values between 0.05 to 10^-6). 

44 genes (16%) changed in both tissues and all overlapping changes were

co-directional.  We are evaluating the overlap of these two gene sets to see if

genes that changed in response to VPA and/or ECS provide novel ways to screen

Targets

for developing improved mood stabilizers have also been identified in human NBFL

neuronal cultures exposed to the primary mood stabilizers, VPA (0.5 mM), lithium

(1.5mM) and carbamazepine (0.3mM).  Because VPA and carbamazepine show strong

anticonvulsant activities, we used phenytoin as a negative control, as it is an

antiepileptic compounds without BD efficacy.  Many gene changes from 1.5 to 3

fold (p values between 0.05 – 10^-7) were validated using Affymetrix

and Agilent microarray platforms, or RT-PCR.  Fourteen genes showing the most

consistent response with these platforms were chosen as targets for drug

screening.  Our Multi-Parameter High Throughput Screen^SM (MPHTS^SM)

measured the effect of 4,800 compounds on the expression of 3 of these genes in

each well of a 96 well plate.  Among the 22 compounds that were active in the 3

initial gene signature, four compounds affected from 3 to 9 of the 14 genes and

at 10-fold lower concentrations than did VPA.  These compounds are being