Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention

Abstract

SummaryNeocortical choline acetyltransferase (ChAT)-expressing interneurons are a subclass of vasoactive intestinal peptide (ChAT-VIP) neurons of which circuit and behavioural function are unknown. It has also not been addressed whether these neurons release both neurotransmitters acetylcholine (ACh) and GABA. Here, we find that in the medial prefrontal cortex (mPFC), ChAT-VIP neurons directly excite interneurons in layers (L)1-3 as well as pyramidal neurons in L2/3 and L6 by fast cholinergic transmission. Dual recordings of presynaptic ChAT-VIP neurons and postsynaptic L1 interneurons show fast nicotinic receptor currents strictly time-locked to single presynaptic action potentials. A fraction (10-20%) of postsynaptic neurons that received cholinergic input from ChAT-VIP interneurons also received GABAergic input from these neurons. In contrast to regular VIP interneurons, ChAT-VIP neurons did not disinhibit pyramidal neurons, but instead depolarized fast spiking and low threshold spiking interneurons. Finally, we find that ChAT-VIP neurons control attention behaviour distinctly from basal forebrain ACh inputs to mPFC. Our findings show that ChAT-VIP neurons are a local source of cortical ACh, that directly excite pyramidal and interneurons throughout cortical layers.

Cortical ChAT+neurons co-transmit acetylcholine and GABA in a target- and brain-region specific manner

“…A recent publication reported rates of GABA and ACh connectivity from cortical ChAT + neurons that were strikingly different from what we described above 28 . They reported that optogenetic activation of cortical ChAT + neurons frequently resulted in postsynaptic cholinergic currents and rarely GABAergic currents.…”

“…Target-specificity is partially specified at the pre-synaptic level, as we identified two distinct populations of pre-synaptic terminals: a subset that are competent to release both GABA and ACh and others that can only release GABA. The second class of cortical ChAT + interneurons is molecularly and functionally distinct from VIP + cholinergic interneurons and was discovered in an effort to reconcile our results with those of another study that described predominantly ACh, and not GABA release, from cortical ChAT + interneurons 28 . This sparse population of non-VIP ChAT + neurons is found in the mPFC, has a distinct developmental origin from VIP interneurons, and contributes primarily cholinergic signaling.…”

“…Von Engelhardt and colleagues reported that cortical ChAT + neurons release ACh that opens nicotinic ACh receptors (nAChRs) on excitatory pre-synaptic terminals to increase synaptic release of glutamate 27 . A recent study by Obermayer et al found that cortical ChAT + neurons directly excite several interneuron subtypes as well as deep layer pyramidal neurons via nAChRs 28 . These studies argue strongly for a primarily cholinergic role for these neurons.…”

“…Several studies have reported GABA synthetic enzyme expression in only a subset of cortical ChAT + neurons 18,27 , whereas others have reported widespread co-labeling with GABA 29 . Although the synaptic outputs of cortical ChAT + neurons have either been described as entirely cholinergic 27 or partially GABAergic 28 , activation of cortical ChAT + neurons in vivo suppresses responses to sensory input 30 . This could occur either through directly via GABAergic inhibition or indirectly by cholinergic excitation of intermediate inhibitory interneurons.…”

Diversity of GABAergic interneurons and diversification of communication modules in cortical networks

“…Sst-Chod1, Sst-Calb2-Pdlim5, Sst-Chrna2-Glra3) are also consistent with previous studies (Figure 1) (18)(19)(20). Certain clusters may correspond to newly discovered types; for example, one of the four clusters defined by VIP and Chat expression might correspond to a type that directly excites layer 1 interneurons and layer 2/3 pyramidal neurons (21).…”