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. 2011 Mar;14(2):157-74.
doi: 10.1017/S1461145710000179. Epub 2010 Mar 3.

Modulation of cell adhesion systems by prenatal nicotine exposure in limbic brain regions of adolescent female rats

Junran Cao  1 , Jennifer B Dwyer, Jamie E Mangold, Ju Wang, Jinxue Wei, Frances M Leslie, Ming D Li
Affiliations

Modulation of cell adhesion systems by prenatal nicotine exposure in limbic brain regions of adolescent female rats

Junran Cao et al. Int J Neuropsychopharmacol. 2011 Mar.

Abstract

Maternal smoking during pregnancy (MS) has long-lasting neurobehavioural effects on the offspring. Many MS-associated psychiatric disorders begin or change symptomatology during adolescence, a period of continuous development of the central nervous system. However, the underlying molecular mechanisms are largely unknown. Given that cell adhesion molecules (CAMs) modulate various neurotransmitter systems and are associated with many psychiatric disorders, we hypothesize that CAMs are altered by prenatal treatment of nicotine, the major psychoactive component in tobacco, in adolescent brains. Pregnant Sprague-Dawley rats were treated with nicotine (3 mg/kg.d) or saline via osmotic mini-pumps from gestational days 4 to 18. Female offspring at postnatal day 35 were sacrificed, and several limbic brain regions (the caudate putamen, nucleus accumbens, prefrontal cortex, and amygdala) were dissected for evaluation of gene expression using microarray and quantitative RT-PCR techniques. Various CAMs including neurexin, immunoglobulin, cadherin, and adhesion-GPCR superfamilies, and their intracellular signalling pathways were modified by gestational nicotine treatment (GN). Among the CAM-related pathways, GN has stronger effects on cytoskeleton reorganization pathways than on gene transcription pathways. These effects were highly region dependent, with the caudate putamen showing the greatest vulnerability. Given the important roles of CAMs in neuronal development and synaptic plasticity, our findings suggest that alteration of CAMs contributes to the neurobehavioural deficits associated with MS. Further, our study underscores that low doses of nicotine produce substantial and long-lasting changes in the brain, implying that nicotine replacement therapy during pregnancy may carry many of the same risks to the offspring as MS.

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Conflict of interest statement

Statement of Interest

None.

Figures

Fig. 1
Fig. 1
Biological pathways significantly modified by gestational nicotine treatment in the adolescent brain regions analysed by GSEA (nominal p<0.05). For each brain region, the pathways were plotted in descending order of the negative logarithm of their p values at base 10. The biological pathways related to cell adhesion molecules are shown in black columns, whereas others are shown in light grey. For each pathway, a short format of its name in the GSEA database is shown in the figure: for amygdala, Gamma_hexachlorocyclohexane and Mitochondrial_fatty_acid are short formats of Gamma_ hexachlorocyclohexane_degradation and Mitochondrial_fatty_acid_betaoxidation, respectively; for NAc, Sig_pip3_signalling corresponds to Sig_pip3_signalling_in_cardiac_myoctes; for PFC, St_T_cell_signal and St_B_cell_antigen are short formats of St_T_cell_signal_transduction and St_B_cell_antigen_receptor, respectively; for PVN, Oxidative_phosph, Glycerolipid and Sa_B_cell_receptor are short formats of Oxidative_phosphorylation, Glycerolipid_metabolism and Sa_B_cell_receptor_ complexes, respectively; for the other pathways, the word pathway has been omitted from their names.
Fig. 2
Fig. 2
Cell adhesion molecules modulate actin cytoskeleton via Rho small GTPases. Genes in red were up-regulated whereas those in green were down-regulated at the mRNA level by gestation nicotine exposure in (a) the caudate putamen, (b) nucleus accumbens, (c) prefrontal cortex and (d) amygdala. * Significantly modified compared with gestational saline treatment (p<0.05 at least). ABI2, abl-interactor 2; ARP2/3, actin-related protein complex; Cdc42, cell division cycle 42; Cofilin, cofilin 1 (non-muscle); GDIA, Rho GDP dissociation inhibitor (GDI) alpha; Gelsolin, gelsolin (amyloidosis, Finnish type); LIMK, LIM domain kinase 1; MLC, myosin light chain; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; PAK, p21-activated protein kinase 1 (Pak1); PIP, 1-phosphatidyl-1D-myo-inositol 4-phosphate; PIP2, 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate; PIP5K, 1-phosphatidylinositol-4-phosphate 5-kinase; Rac, ras-related C3 botulinum toxin substrate 1 (Rac1); Rho, ras homolog gene family, member A (RhoA); ROCK, Rho-associated, coiled-coil containing protein kinase 1 (Rock1); WASP, Wiskott–Aldrich syndrome-like (N-WASP); WAVE, WAS protein family.
Fig. 2
Fig. 2
Cell adhesion molecules modulate actin cytoskeleton via Rho small GTPases. Genes in red were up-regulated whereas those in green were down-regulated at the mRNA level by gestation nicotine exposure in (a) the caudate putamen, (b) nucleus accumbens, (c) prefrontal cortex and (d) amygdala. * Significantly modified compared with gestational saline treatment (p<0.05 at least). ABI2, abl-interactor 2; ARP2/3, actin-related protein complex; Cdc42, cell division cycle 42; Cofilin, cofilin 1 (non-muscle); GDIA, Rho GDP dissociation inhibitor (GDI) alpha; Gelsolin, gelsolin (amyloidosis, Finnish type); LIMK, LIM domain kinase 1; MLC, myosin light chain; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; PAK, p21-activated protein kinase 1 (Pak1); PIP, 1-phosphatidyl-1D-myo-inositol 4-phosphate; PIP2, 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate; PIP5K, 1-phosphatidylinositol-4-phosphate 5-kinase; Rac, ras-related C3 botulinum toxin substrate 1 (Rac1); Rho, ras homolog gene family, member A (RhoA); ROCK, Rho-associated, coiled-coil containing protein kinase 1 (Rock1); WASP, Wiskott–Aldrich syndrome-like (N-WASP); WAVE, WAS protein family.
Fig. 3
Fig. 3
Gene transcription pathways related to cell adhesion molecules. Genes in red were up-regulated whereas those in green were down-regulated at the mRNA level by gestation nicotine exposure in (a) the caudate putamen, (b) nucleus accumbens, (c) prefrontal cortex and (d) amygdala. * Significantly modified compared with gestational saline treatment (p<0.05 at least). APC, adenomatous polyposis coli; Axin, axin 1; B-Raf, v-raf murine sarcoma viral oncogene homolog B1; c-Raf, v-raf-1 murine leukemia viral oncogene homolog 1; C3G, Rap guanine nucleotide exchange factor 1; Calpain, M calpain; CAS, breast cancer anti-estrogen resistance 1; CNTN1, contactin 1; CRKL, v-crk sarcoma virus CT10 oncogene homolog (avian)-like; Delta/Jagged, Notch ligand delta or jagged; Dsh, disheveled; FAK, PTK2 protein tyrosine kinase 2; Frizzled, frizzled homolog 1 (Drosophila); Fyn, FYN oncogene related to SRC, FGR, YES; GBP, frequently rearranged in advanced T-cell lymphomas; GRB2, growth factor receptor-bound protein 2; GSK3, glycogen synthase kinase 3; ILK, integrin-linked kinase; JNK1, mitogen-activated protein kinase 8; MKK4, mitogen-activated protein kinase kinase 4; MLCK, myosin light chain kinase; MLK3, mitogen-activated protein kinase kinase kinase 11; Notch, Notch gene homolog 1 (Notch 1); PAK, p21-activated protein kinase 1 (Pak1); PI3K, phosphatidylinositol 3-kinase; PP2A, protein phosphatase type 2a; R-Ras, related RAS viral (r-ras) oncogene homolog; RAP, RAS-related protein 1a; Ras, Harvey rat sarcoma viral (v-Ha-ras) oncogene homolog; SHC, SHC (Src homology 2 domain containing) transforming protein 1; SOS, son of sevenless homolog; Src, v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian); TACE, ADAM metallopeptidase domain 17; Wnt, wingless-type MMTV integration site family, member 1 (Wnt1); β-catenin, cadherin-associated protein, beta.
Fig. 3
Fig. 3
Gene transcription pathways related to cell adhesion molecules. Genes in red were up-regulated whereas those in green were down-regulated at the mRNA level by gestation nicotine exposure in (a) the caudate putamen, (b) nucleus accumbens, (c) prefrontal cortex and (d) amygdala. * Significantly modified compared with gestational saline treatment (p<0.05 at least). APC, adenomatous polyposis coli; Axin, axin 1; B-Raf, v-raf murine sarcoma viral oncogene homolog B1; c-Raf, v-raf-1 murine leukemia viral oncogene homolog 1; C3G, Rap guanine nucleotide exchange factor 1; Calpain, M calpain; CAS, breast cancer anti-estrogen resistance 1; CNTN1, contactin 1; CRKL, v-crk sarcoma virus CT10 oncogene homolog (avian)-like; Delta/Jagged, Notch ligand delta or jagged; Dsh, disheveled; FAK, PTK2 protein tyrosine kinase 2; Frizzled, frizzled homolog 1 (Drosophila); Fyn, FYN oncogene related to SRC, FGR, YES; GBP, frequently rearranged in advanced T-cell lymphomas; GRB2, growth factor receptor-bound protein 2; GSK3, glycogen synthase kinase 3; ILK, integrin-linked kinase; JNK1, mitogen-activated protein kinase 8; MKK4, mitogen-activated protein kinase kinase 4; MLCK, myosin light chain kinase; MLK3, mitogen-activated protein kinase kinase kinase 11; Notch, Notch gene homolog 1 (Notch 1); PAK, p21-activated protein kinase 1 (Pak1); PI3K, phosphatidylinositol 3-kinase; PP2A, protein phosphatase type 2a; R-Ras, related RAS viral (r-ras) oncogene homolog; RAP, RAS-related protein 1a; Ras, Harvey rat sarcoma viral (v-Ha-ras) oncogene homolog; SHC, SHC (Src homology 2 domain containing) transforming protein 1; SOS, son of sevenless homolog; Src, v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian); TACE, ADAM metallopeptidase domain 17; Wnt, wingless-type MMTV integration site family, member 1 (Wnt1); β-catenin, cadherin-associated protein, beta.
Fig. 4
Fig. 4
A proposed neuronal mechanism underlying the neurobehavioural effects of maternal smoking during pregnancy on the adolescent offspring via cell adhesion systems. Animal model of gestational nicotine treatment (GN), which mimics human maternal smoking during pregnancy, showed significant alterations of cell adhesion molecules (CAMs), and CAM downstream signalling pathways, including cytoskeleton reorganization-related and transcription-related pathways. The effects of GN were heterogeneous among the limbic brain regions examined. Given that CAM systems play important roles in synaptic plasticity and myelination, the potential effects of altered CAM systems on the prefrontal cortex (PFC), amygdala (Amy), caudate putamen (CPu), and nucleus accumbens (NAc) were hypothesized. The dotted lines between each brain region indicate connections actively maturing in adolescence and solid lines are connections thought to be mature by adolescence. Up- or down-regulation on each neuronal process is shown by ↑ or ↓, respectively. Given the obvious neurobehavioural consequences of maternal smoking, and strong genetic associations between CAM-related genes and neuropsychiatric disorders, the alterations of CAM systems by GN in the limbic brain regions suggest a new mechanism underling MS-linked neurobehavioural deficits.
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