Characterization of VIP+ interneurons in the mouse whisker barrel cortex during development

Thesis

GABAergic interneurons (INs) are thought to be important players in normal cortical circuit development, with a body of data highlighting the role of two major IN classes – parvalbumin and somatostatin-positive (PV+ and SST+) subtypes – in neonatal mouse sensory cortices (Marques-Smith et al., 2016; Takesian and Hensch, 2013; Tuncdemir et al., 2016). More recent evidence supports a developmental role for a third class of IN, defined by the expression of vasoactive intestinal peptide (VIP+ INs) (Batista-Brito et al., 2017; Goff and Goldberg, 2019; Mossner et al., 2017). This IN subtype has been shown to play a role in sensorimotor integration via preferential targeting of SST+ cells and consequent disinhibition of pyramidal cells in the mature cortex (e.g., Lee et al., 2013). However, it is unknown how and when VIP+ INs integrate into the local and long-range circuitry during early development.

To address this, I first investigated the integration of VIP+ cells into the local circuit in postnatal whisker barrel cortex (S1BF). Data show that, while VIP+ INs acquire mature electrophysiological properties and integrate in the local glutamatergic network over the first two postnatal weeks, they engage with other INs and pyramidal cells already in the first postnatal week. Second, I employed a viral optogenetic strategy to test the emergence of long-range inputs from anterior-motor areas onto S1BF VIP+ cells. Data show that VIP+ INs start to be recruited already in the first postnatal week, but they are fully integrated in the long-range circuitry only at the end of the second postnatal week.

Finally, I have used the VIP-Cre;Prox1^c/c conditional knockout model (Miyoshi et al., 2015) to investigate whether genetic perturbation of VIP+ INs has an impact on synaptic integration and in vivo activity. Data suggest that conditional deletion of Prox1 leads to reorganisation of the local but not long-range glutamatergic input, and increased activity upon whisker stimulation. These findings define the emergence of the VIP+ circuitry and show their early influence in circuit maturation, further supporting the importance of IN signalling in cortical development.

Authors: Vagnoni, C

• DOI: 10.5287/ora-zrpeqy6r1
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: long-range; cortical development; interneuron; VIP; vasoactive intestinal peptide; Prox1; connectivity
• Subjects: Developmental neurobiology