Abstract
During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines.
Highlights
The cerebral cortex receives synaptic inputs from various cortical and subcortical areas including the thalamus
Hevin is expressed throughout the cortex in a developmentally regulated manner, peaking during P15–P25, a time period that coincides with intense synapse formation, maturation and elimination events in the cortex (Figure 1A,B)
Wherein appropriate synapses are strengthened while superfluous connections are eliminated, are critical for the establishment of functional neuronal circuitry
Summary
The cerebral cortex receives synaptic inputs from various cortical and subcortical areas including the thalamus. Innervation of the cortex by projecting neurites called axons begins during embryonic development and continues for the first several postnatal days (Garel and Lopez-Bendito, 2014). After the axons project to their approximate target areas, hosting their suitable postsynaptic partners, does an intense period of synapse formation occur, corresponding roughly to the second and third postnatal weeks in mice (Li et al, 2010). Cortical excitatory synapses, which primarily use the neurotransmitter glutamate, are formed between dendritic protrusions called spines and axonal projections coming from two predominant inputs: intracortical and thalamic. Though the bulk of the cortical synapses from both of these inputs are made during the same early postnatal synaptogenic period (P5–P21) (Nakamura et al, 2005), whether they form through similar or differential mechanisms is unclear.
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