Ontogeny of the VIP+ interneuron sensory-motor circuit prior to active whisking

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Development of the cortical circuits for sensory-motor processing require the coordinated integration of both columnar and long-range synaptic connections. To understand how this occurs at the level of individual neurons we have explored the timeline over which vasoactive intestinal peptide (VIP)-expressing interneurons integrate into mouse somatosensory cortex. We find a distinction in emergent long-range anterior-motor and columnar glutamatergic inputs onto layer (L)2 and L3 VIP+ interneurons respectively. In parallel, VIP+ interneurons form efferent connections onto both pyramidal cells and interneurons in the immediate column in an inside-out manner. Cell-autonomous deletion of the fate-determinant transcription factor, <jats:italic>Prox1</jats:italic>, spares long-range anterior-motor inputs onto VIP+ interneurons, but leads to deficits in local connectivity. This imbalance in the somatosensory circuit results in altered spontaneous and sensory-evoked cortical activity <jats:italic>in vivo</jats:italic>. This identifies a critical role for VIP+ interneurons, and more broadly interneuron heterogeneity, in formative circuits of neocortex.</jats:p>

Contribution of interneuron subtype-specific GABAergic signalling to emergent sensory processing in somatosensory whisker barrel cortex in mouse

“…However, in the case of VIP+ INs this is counterintuitive given the body of data that suggest these cells exert a primarily dis-inhibitory effect on pyramidal cells via the inhibition of SST+ INs (Pfeffer et al, 2013; Pi et al, 2013). That said, this observation echoes recent findings that suggest that VIP+ INs directly inhibit pyramidal cells in a state-dependent manner (Batista-Brito et al, 2017; Vagnoni et al, 2020). Moreover, it is clear from the effect of silencing INs on spontaneous activity that VIP+ INs develop to control spontaneous pyramidal cell activity around the onset of active whisking.…”

“…However, this effect was mostly in the lower, infragranular layers. We did not observe any change in supragranular layer activity, in line with the late integration of VIP+ INs in the local network (Batista-Brito et al, 2017; Vagnoni et al, 2020). Before the onset of active sensation, VIP+ IN silencing led to a transient increase in sensory response in the granular layer.…”

“…We performed multi-electrode in vivo electrophysiology to record both local field potential (LFP) and multi-unit activity (MUA) across the depth of S1BF in response to multi-whisker stimulation across early development. We divided our analysis into three developmental time windows: postnatal day (P)5-P8 (equivalent to the layer 4 critical period for plasticity; CP), the next few days prior to active perception (P9-P11; pre-active whisking; pre-AW) and a time window covering the onset of active perception (P12-P16; active whisking; AW); windows that reflect our existing knowledge of underlying circuitry from in vitro studies (Anastasiades & Butt, 2012; Anastasiades et al, 2016; Vagnoni et al, 2020). Our initial analysis focused on granular layer 4 (G) as this layer showed robust LFP and MUA across all three developmental time points ( Figure 1A , B ).…”

“…Xu, Roby, & Callaway, 2010). Moreover, in vitro data has identified the presence of transient translaminar networks mediated by both subtypes during early postnatal life (Marques-Smith et al, 2016; Vagnoni et al, 2020). During the CP time window, MUA is largely confined to granular L4.…”

“…These are born late in embryonic development (S. Butt et al, 2005; Miyoshi et al, 2015) and as such are thought to contribute to circuit refinement towards the onset of active sensory perception (Hanganu-Opatz et al, 2021). That said, one major subtype of 5-HT 3A R IN - the genetically-tractable vasoactive intestinal peptide-positive (VIP+) INs, have recently been shown to influence early circuits via their interaction with pyramidal cells and SST+ INs (Batista-Brito et al, 2017; Marques-Smith et al, 2016; Tuncdemir et al, 2016; Vagnoni et al, 2020). Based on this understanding, we hypothesised that both SST+ and VIP+ INs contribute to emergent sensory processing through postnatal life; a role that we can test using conditional silencing of neurotransmitter release via deletion of the SNARE complex protein Snap25 (Marques-Smith et al, 2016; Washbourne et al, 2002).…”