A new study highlights the selective role of astrocytes, a type of glial cell, in regulating synaptic connections within the striatum, a brain region pivotal for motor control and learning.
Scientists have discovered distinct mechanisms by which astrocytes target and eliminate specific types of excitatory synapses, particularly prioritizing corticostriatal synapses over thalamostriatal ones. This research sheds light on the potential role astrocytes play not only during brain development but also how they help maintain synaptic homeostasis and plasticity throughout adulthood.
Using model mice genetically modified to lack astrocytic phagocytosis receptors, researchers determined the functional significance of astrocytes' synaptic pruning roles. The study revealed the continuous removal of corticostriatal synapses, emphasizing the importance of these cells not only for brain structure but for its function, especially concerning learning processes.
The findings emerged from detailed electrophysiological examinations which included measuring spontaneous excitatory postsynaptic currents (sEPSCs) from medium spiny neurons (MSNs) within the dorsal striatum. The results indicated significantly higher frequencies of sEPSCs in the modified mice compared to controls, implying disrupted synaptic connectivity.
The research utilized double-loxP-floxed Megf10 and Mertk (MEGF10/MERTK) knockouts to effectively inhibit astrocyte phagocytosis, leading to significant alterations in synapse density. Specifically, increases were observed in VGLUT1 (markers for cortical-derived synapses) density and VGLUT1+Homer1-positive synapses within the dorsal striatum of the astrocytic receptor-deficient mice.
Importantly, the data demonstrated how these deficits affected the performance of the modified mice during motor skill learning tasks. One such task, the Rotarod test, showed reduced learning capabilities during early trials among the DAPS (Depletion of Astrocytic Phagocytosis in the Striatum) mice, compared to their control counterparts.
Further testing with optogenetic stimulation and theta-burst stimulation (TBS) revealed diminished long-term potentiation (LTP) of corticostriatal synapses associated with motor skill learning when astrocytic phagocytosis was inhibited. Researchers noted the importance of these phagocytic mechanisms during the early phases of motor skill acquisition, as indicated by delayed performance improvements noted within the trial sessions.
This research suggests astrocytic phagocytosis is not merely incidental but instrumental to the effective execution of neural circuits related to learning and memory. The pathway for astrocytic synapse targeting involves MEGF10 and MERTK phagocytic receptors, pointing to these cells as active participants within synaptic networks, much like neurons themselves.
Astrocytes appear to contribute significantly to maintaining the exquisite balance of excitatory and inhibitory connections required for proper brain function by selectively engulfing or eliminating excessive excitatory synapses. Understanding the mechanisms by which astrocytes discern which synapses to prune is fundamental for future neuroscience studies, particularly those aiming to address neurological disorders linked to synaptic regulation.
With potential future research directions, this investigation highlights the necessity of continuing to explore astrocytic roles beyond passive support within the CNS, envisioning them as active agents in neural circuit dynamics.