This is a very interesting paper. Karine Guillem and colleagues report a new discovery that the β2*-nicotinic acetylcholine receptors (nAChRs) likely play a critical role in the mediation of endogenous cholinergic modulations of animal attentional performance. A large body of evidence shows that α7-nAChRs play important roles in mediating cholinergic modulations of animal cognitive activity. However, in this paper, the authors have provided clear evidence that the β2*-, but not α7-nAChRs in the prelimbic (PrL) prefrontal cortex (PFC) are important for attentional performance. I have several personal suggestions for some further investigations that may improve our understanding of nicotinic effects on cognitive function.
Post-synaptic effect: In this paper, the authors showed evidence (patch-clamp whole-cell currents) that post-synaptic (somatodendritic) β2*-nAChRs are important since restored β2*-nAChRs improved attentional performance in nAChR β2 knockout mice. However, a previous publication by the same group (Couey et al., 2007) mentioned that nAChRs (especially β2*-nAChRs) are predominantly expressed in interneurons rather than pyramidal neurons in layer V of the PFC (also see Ji et al., 2008). Interestingly, in PFC layer VI, pyramidal neurons express nAChRs that may include β2*-nAChRs (Alves et al., 2010; Kassam et al., 2008). Therefore, it will be interesting to identify the importance of the location and distribution of β2*-nAChRs in different types of cells and different layers of the PFC in animal attentional performance.
Pre-synaptic effect: It has been known that pre-synaptic nAChRs including both β2*-nAChRs and α7-nAChRs modulate glutamate release onto pyramidal neurons of PFC layer V, which may be an important source for maintaining excitatory tone over pyramidal neuron activity under endogenous cholinergic control (Dickinson et al., 2008; Parikh et al., 2010). It will be interesting to see the alterations of PFC pre-synaptic glutamate release (e.g., EPSCs in layer V pyramidal neurons) in the nAChR β2 knockout mice that exhibit impairment of attentional performance.
nAChR subunit compensation: Previous reports and our own data showed that in nAChR β2 knockout mice, α7-nAChR function is significantly enhanced (Wooltorton et al., 2003; Liu et al., 2009). Considering the critical roles played by the α7-nAChRs in the modulation of cognitive function, it will be interesting to see whether enhanced α7-nCAhR function can enhance animal attentional performance.
Interaction with other receptors: In another current paper published by the same group, the authors provide evidence that metabotropic glutamate receptor (mGluR2) on glutamatergic pre-synaptic terminals of the PFC play a key role in nicotine-induced lasting attentional disturbances (Counotte et al., 2011). It will be interesting to test the relationship between nAChRs (β2*-nAChRs) and glutamate receptors in animal attentional performance. For instance, is it possible that β2*-nAChRs play a role in modulation of glutamate receptor expression and function?
References:
Couey JJ, Meredith RM, Spijker S, Poorthuis RB, Smit AB, Brussaard AB, Mansvelder HD.
Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex.
Neuron. 2007 Apr 5;54(1):73-87.
PubMed.
Ji XH, Cao XH, Zhang CL, Feng ZJ, Zhang XH, Ma L, Li BM.
Pre- and postsynaptic beta-adrenergic activation enhances excitatory synaptic transmission in layer V/VI pyramidal neurons of the medial prefrontal cortex of rats.
Cereb Cortex. 2008 Jul;18(7):1506-20.
PubMed.
Alves NC, Bailey CD, Nashmi R, Lambe EK.
Developmental sex differences in nicotinic currents of prefrontal layer VI neurons in mice and rats.
PLoS One. 2010;5(2):e9261.
PubMed.
Kassam SM, Herman PM, Goodfellow NM, Alves NC, Lambe EK.
Developmental excitation of corticothalamic neurons by nicotinic acetylcholine receptors.
J Neurosci. 2008 Aug 27;28(35):8756-64.
PubMed.
Dickinson JA, Kew JN, Wonnacott S.
Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms.
Mol Pharmacol. 2008 Aug;74(2):348-59.
PubMed.
Parikh V, Ji J, Decker MW, Sarter M.
Prefrontal beta2 subunit-containing and alpha7 nicotinic acetylcholine receptors differentially control glutamatergic and cholinergic signaling.
J Neurosci. 2010 Mar 3;30(9):3518-30.
PubMed.
Wooltorton JR, Pidoplichko VI, Broide RS, Dani JA.
Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas.
J Neurosci. 2003 Apr 15;23(8):3176-85.
PubMed.
Liu Q, Huang Y, Xue F, Simard A, Dechon J, Li G, Zhang J, Lucero L, Wang M, Sierks M, Hu G, Chang Y, Lukas RJ, Wu J.
A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides.
J Neurosci. 2009 Jan 28;29(4):918-29.
PubMed.
Counotte DS, Goriounova NA, Li KW, Loos M, van der Schors RC, Schetters D, Schoffelmeer AN, Smit AB, Mansvelder HD, Pattij T, Spijker S.
Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence.
Nat Neurosci. 2011 Apr;14(4):417-9.
PubMed.
Comments
Barrow Neurological Institute
This is a very interesting paper. Karine Guillem and colleagues report a new discovery that the β2*-nicotinic acetylcholine receptors (nAChRs) likely play a critical role in the mediation of endogenous cholinergic modulations of animal attentional performance. A large body of evidence shows that α7-nAChRs play important roles in mediating cholinergic modulations of animal cognitive activity. However, in this paper, the authors have provided clear evidence that the β2*-, but not α7-nAChRs in the prelimbic (PrL) prefrontal cortex (PFC) are important for attentional performance. I have several personal suggestions for some further investigations that may improve our understanding of nicotinic effects on cognitive function.
References:
Couey JJ, Meredith RM, Spijker S, Poorthuis RB, Smit AB, Brussaard AB, Mansvelder HD. Distributed network actions by nicotine increase the threshold for spike-timing-dependent plasticity in prefrontal cortex. Neuron. 2007 Apr 5;54(1):73-87. PubMed.
Ji XH, Cao XH, Zhang CL, Feng ZJ, Zhang XH, Ma L, Li BM. Pre- and postsynaptic beta-adrenergic activation enhances excitatory synaptic transmission in layer V/VI pyramidal neurons of the medial prefrontal cortex of rats. Cereb Cortex. 2008 Jul;18(7):1506-20. PubMed.
Alves NC, Bailey CD, Nashmi R, Lambe EK. Developmental sex differences in nicotinic currents of prefrontal layer VI neurons in mice and rats. PLoS One. 2010;5(2):e9261. PubMed.
Kassam SM, Herman PM, Goodfellow NM, Alves NC, Lambe EK. Developmental excitation of corticothalamic neurons by nicotinic acetylcholine receptors. J Neurosci. 2008 Aug 27;28(35):8756-64. PubMed.
Dickinson JA, Kew JN, Wonnacott S. Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms. Mol Pharmacol. 2008 Aug;74(2):348-59. PubMed.
Parikh V, Ji J, Decker MW, Sarter M. Prefrontal beta2 subunit-containing and alpha7 nicotinic acetylcholine receptors differentially control glutamatergic and cholinergic signaling. J Neurosci. 2010 Mar 3;30(9):3518-30. PubMed.
Wooltorton JR, Pidoplichko VI, Broide RS, Dani JA. Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas. J Neurosci. 2003 Apr 15;23(8):3176-85. PubMed.
Liu Q, Huang Y, Xue F, Simard A, Dechon J, Li G, Zhang J, Lucero L, Wang M, Sierks M, Hu G, Chang Y, Lukas RJ, Wu J. A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides. J Neurosci. 2009 Jan 28;29(4):918-29. PubMed.
Counotte DS, Goriounova NA, Li KW, Loos M, van der Schors RC, Schetters D, Schoffelmeer AN, Smit AB, Mansvelder HD, Pattij T, Spijker S. Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence. Nat Neurosci. 2011 Apr;14(4):417-9. PubMed.
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