Acetylcholine (ACh) is a neurotransmitter critical for normal cognition. Here we demonstrate heterogeneity of cholinergic signalling in neocortical neurons in the rat prefrontal, somatosensory, and visual cortex. Focal ACh application (100 μM) inhibited layer 5 pyramidal neurons in all cortical areas via activation of an apamin-sensitive SK-type calcium-activated potassium conductance. Cholinergic inhibition was most robust in prefrontal layer 5 neurons, where it relies on the same signal transduction mechanism (M1-like receptors, IP3-dependent calcium release, and SK-channels) as exists in somatosensory pyramidal neurons. Pyramidal neurons in layer 2⁄3 were less responsive to ACh, but substantial apamin-sensitive inhibitory responses occurred in deep layer 3 neurons of the visual cortex. ACh was only inhibitory when presented near the somata of layer 5 pyramidal neurons, where repetitive ACh applications generated discrete inhibitory events at frequencies of up to ∼0.5 Hz. Fast spiking (FS) nonpyramidal neurons in all cortical areas were unresponsive to ACh. When applied to non-FS interneurons in layers 2⁄3 and 5, ACh generated mecamylamine-sensitive nicotinic responses (38% of cells), apamin-insensitive hyperpolarizing responses, with or without initial nicotinic depolarization (7% of neurons), or no response at all (55% of cells). Responses in interneurons were similar across cortical layers and regions, but were correlated with cellular physiology and the expression of biochemical markers associated with different classes of nonpyramidal neurons. Finally, ACh generated nicotinic responses in all layer 1 neurons tested. These data demonstrate that phasic cholinergic input can directly inhibit projection neurons throughout the cortex while sculpting intracortical processing, especially in superficial layers.
Gulledge AT, Park SB, Kawaguchi Y, Stuart GJ (2007) Heterogeneity of phasic cholinergic signalling in neocortical neurons. J. Neurophysiol. 97, 2215-2229.
Comparison of transient cholinergic responses in pyramidal neurons in multiple cortical regions and layers. Representative responses of neocortical pyramidal neurons in different layers of the medial prefrontal cortex, somatosensory, and visual cortex to acetylcholine (ACh) application (100 μM, 20 ms).
Summary of phasic actions of ACh on neocortical neurons.
[Above] Diagram showing several classes of neocortical neurons and their responsiveness to ACh. Red upward arrows indicate cell-types exhibiting nAChR-mediated excitation to focal ACh application while blue downward arrows indicate cell-types inhibited via mAChR activation.
[Below] Representative traces showing the effect of ACh on the various cell-types shown in above.
