Long-lasting synaptic regulation of dopamine neurons by astrocytes in the Ventral Tegmental Area

The plasticity of glutamatergic transmission in the Ventral Tegmental Area (VTA) represents a fundamental mechanism in the modulation of dopamine neuron burst firing and the phasic dopamine release at VTA target regions. These processes encode basic behavioral responses, including locomotor activity, learning and motivated-behaviors. Here we describe a hitherto unidentified mechanism of long-lasting potentiation of glutamatergic synapses on DA neurons. We found that VTA astrocytes respond to dopamine neuron bursts with Ca2+ elevations that require activation of endocannabinoid CB1 and dopamine D2 receptors colocalized at the same astrocytic process. Astrocytes, in turn, release glutamate that, through presynaptic metabotropic glutamate receptor activation coupled with neuronal nitric oxide production, induces long-lasting potentiation of excitatory synapses on adjacent dopamine neurons. Consistent with this finding, selective activation of VTA astrocytes increases dopamine neuron bursts in vivo and induces locomotor hyperactivity. Astrocytes play, therefore, a key role in the modulation of VTA dopamine neuron activity.

Amyloid pathology disrupts gliotransmitter release in astrocytes

Accumulation of amyloid-β peptide (Aβ), a hallmark of Alzheimer’s disease (AD), is associated with synchronous hyperactivity and dysregulated Ca2+ signaling in hippocampal astrocytes. However, the consequences of altered Ca2+ signaling on the temporal dynamics of Ca2+ and gliotransmitter release events at astrocytic microdomains are not known. We have developed a detailed biophysical model of microdomain signaling at a single astrocytic process that accurately describes key temporal features of Ca2+ events and Ca2+-mediated kiss-and-run and full fusion exocytosis. Using this model, we ask how aberrant plasma-membrane Ca2+ pumps and mGluR activity, molecular hallmarks of Aβ toxicity that are also critically involved in Ca2+ signaling, modify astrocytic feedback at a tripartite synapse. We show that AD related molecular pathologies increase the rate and synchrony of Ca2+ and exocytotic events triggered by neuronal activity. Moreover, temporal precision between Ca2+ and release events, a mechanism indispensable for rapid modulation of synaptic transmission by astrocytes, is lost in AD astrocytic processes. Our results provide important evidence on the link between AD-related molecular pathology, dysregulated calcium signaling and gliotransmitter release at an astrocytic process.

Focal adhesion molecules regulate astrocyte morphology and glutamate transporters to suppress seizure-like behavior

Astrocytes are important regulators of neural circuit function and behavior in the healthy and diseased nervous system. We screened for molecules in Drosophila astrocytes that modulate neuronal hyperexcitability and identified multiple components of focal adhesion complexes (FAs). Depletion of astrocytic Tensin, β-integrin, Talin, focal adhesion kinase (FAK), or matrix metalloproteinase 1 (Mmp1), resulted in enhanced behavioral recovery from genetic or pharmacologically induced seizure. Overexpression of Mmp1, predicted to activate FA signaling, led to a reciprocal enhancement of seizure severity. Blockade of FA-signaling molecules in astrocytes at basal levels of CNS excitability resulted in reduced astrocytic coverage of the synaptic neuropil and expression of the excitatory amino acid transporter EAAT1. However, induction of hyperexcitability after depletion of FA-signaling components resulted in enhanced astrocyte coverage and an approximately twofold increase in EAAT1 levels. Our work identifies FA-signaling molecules as important regulators of astrocyte outgrowth and EAAT1 expression under normal physiological conditions. Paradoxically, in the context of hyperexcitability, this pathway negatively regulates astrocytic process outgrowth and EAAT1 expression, and their blockade leading to enhanced recovery from seizure.