Target-specific co-transmission of acetylcholine and GABA from a subset of cortical VIP⁺ interneurons

Abstract

The modulation of cortex by acetylcholine (ACh) is typically thought to originate from long-range projections arising in the basal forebrain. However, a subset of VIP interneurons express ChAT, the synthetic enzyme for ACh, and are a potential local source of cortical ACh. Which neurotransmitters these VIP/ChAT interneurons (VCINs) release is unclear, and which post-synaptic cell types these transmitters target is not known. Using quantitative molecular analysis of VCIN pre-synaptic terminals, we show expression of the molecular machinery to release both ACh and GABA, with ACh release restricted to a subset of boutons. A systematic survey of potential post-synaptic cell types shows that VCINs release GABA primarily onto other inhibitory interneuron subtypes, while ACh neurotransmission is notably sparse, with most ACh release onto layer 1 interneurons and other VCINs. Therefore, VCINs are an alternative source of cortical ACh signaling that supplement GABA-mediated disinhibition with highly targeted excitation through ACh.

Barrel cortex VIP/ChAT interneurons suppress sensory responses in vivo

“…Our results correspond with Arroyo and colleagues (2012), who show in vitro that the activation of VChIs causes a barrage of inhibitory postsynaptic currents (IPSCs) in neighboring Pyrs in the sensorimotor cortex [46]. Two recent studies [9,10] used optogenetics and electrophysiology in vitro to study the local output connectivity pattern of cortical VChIs. Interestingly, both studies demonstrated a release of ACh from VChI output synapses.…”

“…The estimates regarding the sparseness of VChIs vary between studies [7,9,11,47]. In order to obtain an independent estimate of the number and the spatial distribution of VChIs, we used immunostaining in wild-type (WT) mice (Fig 1A and 1B; see Materials and methods).…”

“…These cortical interneurons are a subgroup of a larger population of interneurons expressing vasoactive intestinal polypeptide (VIP). As such, the cortical VIP/ChAT interneurons (VChIs) can corelease both γ-aminobutyric acid (GABA) and acetylcholine (ACh) [5][6][7][8][9][10][11].…”

“…Later, Arroyo and colleagues (2012) demonstrated that optogenetic activation of the BF excites VChIs, which in turn causes inhibitory currents in Pyrs [46]. Recent studies combining optogenetics and electrophysiology in the mouse frontal and visual cortex showed that VChIs have a specific output connectivity pattern, as they preferentially target layer 1 and layer 6 neurons, as well as the SST + subpopulation [9,10]. These studies also measured both nicotinic and GABAergic currents, confirming that VChIs do form synapses that release both ACh and GABA.…”

Morphometric reconstructions atlas shows insult-driven plasticity in cortical VIP/ChAT interneurons

“…The morphology and distribution of VChI neurons were recently described and categorized based on two distinct morphological sub-populations, bipolar/bi-tufted and multipolar 25,34,35 .…”