Astrocyte Signaling Gates Long-Term Depression at Corticostriatal Synapses of the Direct Pathway

Area of Science:

• Neuroscience
• Cellular Biology
• Synaptic Plasticity

Background:

• Striatal plasticity is vital for motor control and is implicated in neurological disorders.
• The role of astrocytes in striatal synaptic plasticity remains largely unknown.
• Astrocytes modulate synaptic transmission via released factors like adenosine in other brain regions.

Purpose of the Study:

• To investigate the contribution of astrocyte-neuron signaling to long-term depression (LTD) at corticostriatal synapses.
• To determine if astrocyte-derived adenosine mediates LTD in the dorsolateral striatum (DLS).
• To elucidate the cellular mechanisms underlying astrocyte involvement in striatal synaptic plasticity.

Main Methods:

• High-frequency stimulation (HFS) of cortical inputs to induce LTD in mouse DLS.
• Measurement of astrocyte calcium (Ca2+) levels using fluorescent indicators.
• Pharmacological manipulation and genetic targeting (DREADDs) of astrocyte signaling pathways.
• Electrophysiological recordings of synaptic transmission at cortico-striatal synapses.

Main Results:

• Cortical HFS induced LTD at direct pathway cortico-striatal synapses, mediated by adenosine A1 receptor (A1R) activation.
• HFS increased astrocyte Ca2+ levels in the DLS via metabotropic glutamate receptor 5 (mGluR5) activation.
• Astrocyte Ca2+ signaling was necessary for A1R-mediated LTD.
• Artificial astrocyte activation using DREADDs induced A1R-mediated synaptic depression.

Conclusions:

• Astrocytes are integral components of A1R-mediated LTD at corticostriatal synapses.
• Neuron-astrocyte signaling, specifically astrocyte Ca2+ responses, is essential for striatal synaptic plasticity.
• These findings underscore the active role of astrocytes in regulating synaptic function and brain circuitry.