Abstract
Astrocytes orchestrate neural development by powerfully coordinating synapse formation and function and, as such, may be critically involved in the pathogenesis of neurodevelopmental abnormalities and cognitive deficits commonly observed in psychiatric disorders. Here, we report the identification of a subset of cortical astrocytes that are competent for regulating dopamine (DA) homeostasis during postnatal development of the prefrontal cortex (PFC), allowing for optimal DA-mediated maturation of excitatory circuits. Such control of DA homeostasis occurs through the coordinated activity of astroglial vesicular monoamine transporter 2 (VMAT2) together with organic cation transporter 3 and monoamine oxidase type B, two key proteins for DA uptake and metabolism. Conditional deletion of VMAT2 in astrocytes postnatally produces loss of PFC DA homeostasis, leading to defective synaptic transmission and plasticity as well as impaired executive functions. Our findings show a novel role for PFC astrocytes in the DA modulation of cognitive performances with relevance to psychiatric disorders.
Highlights
The presence of bona fide genes involved in the synthesis, uptake, storage and degradation of DA was here investigated in purified astrocytes micro-dissected, postnatal day 40 (P40) frontal cortex by means of fluorescence activated cell sorting (FACS) and GFAPECFP [31] or ALDH1L1-EGFP [32] transgene reporter mice
The vesicular monoamine transporter 2 (VMAT2) signal was readily recognizable in the cell bodies and large processes of glutamine synthase (GS)-positive astrocytes located in the frontal regions (Fig. 1b), but the signal was respectively weak or virtually absent in the striatum (ST) and ventral tegmental area (VTA) (Fig. 1c)
Fold less than in DAergic axons but still significantly above background (+82%) calculated in mitochondria (n = 3 rats; one-way ANOVA, Bonferroni’s post-test correction, *p < 0.05). These findings indicate that organic cation transporter 3 (OCT3), VMAT2 and monoamine oxidase B (MAOB) are present in prefrontal cortex (PFC) astrocytes and may contribute to the regulation of DA homeostasis
Summary
Executive functions develop throughout childhood and adolescence, and the appropriate maturation of the circuitry within PFC may play a key role in this trajectory [2] Consistent with this notion, impairments in executive functions are central symptoms associated with developmental neuropsychiatric disorders such as schizophrenia and autism spectrum disorders [1], suggesting that alterations in the development of synaptic circuitries in the PFC play a central role in the pathophysiology of psychiatric disorders with shared deficits in executive functions. In the PFC, DA innervation and receptor expression are present early in development, mature during adolescence and form stable patterns in adulthood This prolonged development timeline provides a large window of 'critical period' during which potential alterations in the mechanisms regulating DA homeostasis can induce a variety of effects including altered spinogenesis and dysfunctional glutamatergic synapses [7, 12] and cognitive dysfunctions [10]. Despite the importance of DA in controlling the development and the functions of the PFC, we are still largely ignoring the cellular mechanisms regulating DA homeostasis and in particular the specific roles that astrocytes may play
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