Developmental Excitation of Corticothalamic Neurons by Nicotinic Acetylcholine Receptors

Abstract

In this study, we show robust nicotinic excitation of pyramidal neurons in layer VI of prefrontal cortex. This layer contains the corticothalamic neurons, which gate thalamic activity and play a critical role in attention. Our experiments tested nicotinic excitation across postnatal development, using whole-cell recordings in prefrontal brain slices from rats. These experiments showed that layer VI neurons have peak nicotinic currents during the first postnatal month, a time period of intensive cortical development in rodents. We demonstrate that these currents are mediated directly by postsynaptic nicotinic receptors and can be suppressed by a competitive antagonist of ␣ 4 ␤ 2 * nicotinic receptors. To record from identified corticothalamic neurons, we performed stereotaxic surgery to label the neurons projecting to medial dorsal thalamus. As hypothesized, recordings from these retrogradely labeled neurons in layer VI showed prominent nicotinic currents. Finally, we examined the effects of the drug nicotine on layer VI neurons and probed for the potential involvement of the accessory subunit, ␣ 5 , in their receptors. A level of nicotine similar to that found in the blood of smokers elicits a stable inward current in layer VI neurons, yet this exposure desensitizes ϳ50% of the subsequent current elicited by acetylcholine. An allosteric modulator of ␣ 4 ␤ 2 ␣ 5 receptors resulted in a 2.5-fold potentiation of submaximal nicotinic currents. This result is consistent with the expression of the relatively rare ␣ 5 nicotinic subunit in layer VI. In summary, we show that layer VI corticothalamic neurons can be strongly excited during development by an unusual subtype of nicotinic receptor.

α4* Nicotinic Acetylcholine Receptors Modulate Experience-Based Cortical Depression in the Adult Mouse Somatosensory Cortex

“…Previous studies have shown that micro-injection or bath application of nicotine can increase the excitability of corticothalamic (Kassam et al, 2008), entorhinal (Tu et al, 2009) and prefrontal cortical neurons (Vidal and Changeux, 1993;Lambe et al, 2003). However as noted previously, nicotine can also depolarize inhibitory cortical neurons (Couey et al, 2007).…”

Nicotinic actions on neuronal networks for cognition: General principles and long-term consequences

“…While so many aspects of pyramidal cell function are well described, nAChRs are rarely found on pyramidal cells in the cortex [55,75]. A recent study has found nAChRs on layer VI pyramidal cells [71] ( Figure 1). This specific population represents pyramidal cells projecting back to the thalamus.…”

“…In the rat PFC, there are strong developmental changes in nicotinic signalling of pyramidal neurons in layer VI. The nicotinic currents recorded from these neurons mediated by α5-containing nAChRs peak at postnatal week 3 [71]. In human brain, the levels of nAChRs also show regionspecific changes in development.…”

“…Thalamocortical glutamatergic transmission to the prefrontal cortex is augmented by the activation of nAChRs [52,55,63,70,71]. Autoradiographic labelling of nAChRs was reduced after lesions in the medial dorsal thalamus (MDT).…”

“…Recently, important new features of nicotinic modulation of cortical circuits have been uncovered. Pyramidal neurons of layer VI contain 5 subunit-containing nAChRs that directly excite these neurons [71]. Despite these findings, large gaps remain in our understanding of nicotinic modulation of cortical circuits involved in cognition.…”