Developmental Sex Differences in Nicotinic Currents of Prefrontal Layer VI Neurons in Mice and Rats

There is a large sex difference in the prevalence of attention deficit disorder; yet, relatively little is known about sex differences in the development of prefrontal attention circuitry. In male rats, nicotinic acetylcholine receptors excite corticothalamic neurons in layer VI, which are thought to play an important role in attention by gating the sensitivity of thalamic neurons to incoming stimuli. These nicotinic currents in male rats are significantly larger during the first postnatal month when prefrontal circuitry is maturing. The present study was undertaken to investigate whether there are sex differences in the nicotinic currents in prefrontal layer VI neurons during development.Using whole cell recording in prefrontal brain slice, we examined the inward currents elicited by nicotinic stimulation in male and female rats and two strains of mice. We found a prominent sex difference in the currents during the first postnatal month when males had significantly greater nicotinic currents in layer VI neurons compared to females. These differences were apparent with three agonists: acetylcholine, carbachol, and nicotine. Furthermore, the developmental sex difference in nicotinic currents occurred despite male and female rodents displaying a similar pattern and proportion of layer VI neurons possessing a key nicotinic receptor subunit.This is the first illustration at a cellular level that prefrontal attention circuitry is differently affected by nicotinic receptor stimulation in males and females during development. This transient sex difference may help to define the cellular and circuit mechanisms that underlie vulnerability to attention deficit disorder

Financial and Psychological Risk Attitudes Associated with Two Single Nucleotide Polymorphisms in the Nicotine Receptor (CHRNA4) Gene

With recent advances in understanding of the neuroscience of risk taking, attention is now turning to genetic factors that may contribute to individual heterogeneity in risk attitudes. In this paper we test for genetic associations with risk attitude measures derived from both the psychology and economics literature. To develop a long-term prospective study, we first evaluate both types of risk attitudes and find that the economic and psychological measures are poorly correlated, suggesting that different genetic factors may underlie human response to risk faced in different behavioral domains. We then examine polymorphisms in a spectrum of candidate genes that affect neurotransmitter systems influencing dopamine regulation or are thought to be associated with risk attitudes or impulsive disorders. Analysis of the genotyping data identified two single nucleotide polymorphisms (SNPs) in the gene encoding the alpha 4 nicotine receptor (CHRNA4, rs4603829 and rs4522666) that are significantly associated with harm avoidance, a risk attitude measurement drawn from the psychology literature. Novelty seeking, another risk attitude measure from the psychology literature, is associated with several COMT (catechol-O-methyl transferase) SNPs while economic risk attitude measures are associated with several VMAT2 (vesicular monoamine transporter) SNPs, but the significance of these associations did not withstand statistical adjustment for multiple testing and requires larger cohorts. These exploratory results provide a starting point for understanding the genetic basis of risk attitudes by considering the range of methods available for measuring risk attitudes and by searching beyond the traditional direct focus on dopamine and serotonin receptor and transporter genes

Association of nicotine dependence susceptibility gene, CHRNA5, with Parkinson's disease age at onset : gene and smoking status interaction

BACKGROUND: Smoking is a well documented environmental factor that reduces susceptibility to Parkinson's disease (PD). Several genetic variants within the nicotinic cholinergic receptor gene cluster, CHRNA5-CHRNA3-CHRNB4 have been reported to be associated with nicotine dependence (ND), and this association has been validated in multiple studies. OBJECTIVES: Due to the inverse correlation between smoking and PD susceptibility, we investigated whether ND-related genetic variants are associated with age at onset (AAO) of PD among smokers. METHODS: We performed a genetic association study in a sample of 677 Italian PD patients, ages 34-76. 438 had never smoked (NS), and 239 were current or past smokers (ever-smokers, ES). Three independent SNPs within the CHRNA5-CHRNA3-CHRNB4 gene cluster (rs588765, rs16969968, rs578776) were analyzed for association with AAO. RESULTS: We demonstrated an interaction between the rs588765 SNP and smoking status (NS vs. ES) that was nominally significant in its effect on PD AAO (p\ua0=\ua00.04). The rs588765 ND risk allele 'C' was associated with delayed AAO among ES (even when smoking intensity variables are accounted for), but had no significant effect among NS. In the ES group, a dominant model of inheritance was observed: carriers of the 'CC' genotype presented delayed AAO compared to carriers of the 'CT' or 'TT' genotypes. CONCLUSION: Our preliminary results suggest that the ND risk variant, rs588765, has a protective effect in PD, and is associated with later AAO, but only when the individual was previously exposed to nicotine. This may be explained by modulating the neuroprotective effect of chronic nicotine exposure against striatal dopaminergic damage. Further validation studies in additional populations are required