Astrocytic VMAT2 in the developing prefrontal cortex is required for normal grooming behavior in mice

Abstract

Astrocytes control synaptic activity by modulating peri-synaptic concentrations of ion and neurotransmitters including dopamine and, as such, can be critically involved in the modulation of some aspect of mammalian behavior. Here we report that genetic mouse model with a reduced medial prefrontal cortex (mPFC) dopamine levels, arising from astrocyte-specific conditional deletion of vesicular monoamine transporter 2 (VMAT2; aVMTA2cKO mice) shows excessive grooming and anxiety-like behaviour. The VMAT2cKO mice also develop a synaptic pathology, expressed through increased relative AMPA vs. NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioural and synaptic phenotypes are prevented by reexpression of mPFC VMAT2, showing that the deficits are driven by mPFC astrocytes. By analysing human tissue samples, we found that VMAT2 is expressed in human mPFC astrocytes, corroborating the potential translational relevance of our observations in mice. Our study shows that impairments of the astrocytic-control of dopamine in the mPFC has a profound impact on circuit function and behaviours, which resemble symptoms of anxiety disorders and obsessive compulsive disorder (OCD).

Emerging evidence for astrocyte dysfunction in schizophrenia

“…A novel mRNA splice variant of Drosophila VMAT (DVMAT‐B) has been found in a small subset of glia in the lamina of the fly's optic lobe (Romero‐Calderón et al, 2008), but it is only very recently that an immunohistochemistry survey of various brain areas has revealed that VMAT2 immunolabeling is particularly enriched in the astrocytes of the frontal cortex (including the PFC) in rodents and humans (Petrelli et al, 2020, 2021). The rodent immunosignal is visible in astrocytes from the second postnatal week, but almost absent in other DAergic areas such as the striatum and ventral tegmental area, which suggests that astrocytic VMAT2 plays a specific functional role in frontal cortical regions.…”

Prolonged Differentiation of Neuron-Astrocyte Co-Cultures Results in Emergence of Dopaminergic Neurons

“…Interestingly, the astrocytes in this model expressed high levels of VMAT2, which do not seem to be present in astrocytes in the SNpc [ 41 ], but only in the prefrontal cortex of mice and potentially humans [ 42 , 43 ]. This suggests that the culture might contain a population of astrocytes resembling the population the dopaminergic neurons project to, rather than the astrocytes in the SNpc.…”

Synapse-specific roles for microglia in development: New horizons in the prefrontal cortex

“…While a large body of work has identified perturbations in neuronal genes and proteins that affect synaptic connectivity (Figures 2A,B; Gauthier et al, 2010;Marín, 2012;Nieto et al, 2013;Volk and Lewis, 2013;El-Ansary and Al-Ayadhi, 2014;McAllister, 2014;English et al, 2015;Estes and McAllister, 2015;Sinclair et al, 2016;Ishizuka et al, 2017;Gao et al, 2018;Jiang et al, 2018;Huang et al, 2019;Trossbach et al, 2019;Wiebe et al, 2019;Barbosa et al, 2020;Chen et al, 2020;Boukouaci et al, 2021), accumulating evidence indicates that microglia are also key loci of dysfunction in neurodevelopmental disorders (Koyama and Ikegaya, 2015;Jin et al, 2017;Comer et al, 2020;Petrelli et al, 2020;Xu et al, 2020). In ASD and SZ, mPFC microglia have amoeboid morphology and increased cytokine production that is characteristic of an activated state (Fillman et al, 2013;Momtazmanesh et al, 2019).…”

“…Indeed, microglial depletion and repopulation can alter astrocyte gene expression (Coleman et al, 2020). Perturbation of astrocyte function has been implicated in ASD and SZ (Trépanier et al, 2016;Tarasov et al, 2020;Zhang et al, 2020;Notter, 2021;Wang et al, 2021;Allen et al, 2022) and astrocyte dysfunction in PFC has been implicated in inducing anxiety-like behaviors (Li et al, 2021) and cognitive impairment (Brockett et al, 2018;Petrelli et al, 2020), making the PFC of particular interest for studying astrocyte-microglial interactions.…”