Gene Expression at the Tripartite Synapse: Bridging the Gap Between Neurons and Astrocytes.

Astrocytes, a major class of glial cells, are an important element at the synapse where they engage in bidirectional crosstalk with neurons to regulate numerous aspects of neurotransmission, circuit function, and behavior. Mutations in synapse-related genes expressed in both neurons and astrocytes are central factors in a vast number of neurological disorders, making the proteins that they encode prominent targets for therapeutic intervention. Yet, while the roles of many of these synaptic proteins in neurons are well established, the functions of the same proteins in astrocytes are largely unknown.

Activity-dependent modulation of synapse-regulating genes in astrocytes.

Astrocytes regulate the formation and function of neuronal synapses via multiple signals; however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals.

Astrocytes, neurons, synapses: a tripartite view on cortical circuit development.

In the mammalian cerebral cortex neurons are arranged in specific layers and form connections both within the cortex and with other brain regions, thus forming a complex mesh of specialized synaptic connections comprising distinct circuits. The correct establishment of these connections during development is crucial for the proper function of the brain. Astrocytes, a major type of glial cell, are important regulators of synapse formation and function during development.

Astrocyte-Secreted Glypican 4 Regulates Release of Neuronal Pentraxin 1 from Axons to Induce Functional Synapse Formation.

The generation of precise synaptic connections between developing neurons is critical to the formation of functional neural circuits. Astrocyte-secreted glypican 4 induces formation of active excitatory synapses by recruiting AMPA glutamate receptors to the postsynaptic cell surface. We now identify the molecular mechanism of how glypican 4 exerts its effect.

A Quantitative Model of the GIRK1/2 Channel Reveals That Its Basal and Evoked Activities Are Controlled by Unequal Stoichiometry of Gα and Gβγ.

G protein-gated K+ channels (GIRK; Kir3), activated by Gβγ subunits derived from Gi/o proteins, regulate heartbeat and neuronal excitability and plasticity. Both neurotransmitter-evoked (Ievoked) and neurotransmitter-independent basal (Ibasal) GIRK activities are physiologically important, but mechanisms of Ibasal and its relation to Ievoked are unclear. We have previously shown for heterologously expressed neuronal GIRK1/2, and now show for native GIRK in hippocampal neurons, that Ibasal and Ievoked are interrelated: the extent of activation by neurotransmitter (activation index, Ra) is inversely related to Ibasal.

The role of neuronal versus astrocyte-derived heparan sulfate proteoglycans in brain development and injury.

Astrocytes modulate many aspects of neuronal function, including synapse formation and the response to injury. Heparan sulfate proteoglycans (HSPGs) mediate some of the effects of astrocytes on synaptic function, and participate in the astrocyte-mediated brain injury response. HSPGs are a highly conserved class of proteoglycans, with variable heparan sulfate (HS) chains that play a major role in determining the function of these proteins, such as binding to growth factors and receptors.

Dual regulation of G proteins and the G-protein-activated K+ channels by lithium.

Lithium (Li(+)) is widely used to treat bipolar disorder (BPD). Cellular targets of Li(+), such as glycogen synthase kinase 3β (GSK3β) and G proteins, have long been implicated in BPD etiology; however, recent genetic studies link BPD to other proteins, particularly ion channels. Li(+) affects neuronal excitability, but the underlying mechanisms and the relevance to putative BPD targets are unknown.