Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex
Significance Synaptic pruning in primate prefrontal cortical circuitry has been proposed to contribute to working memory maturation. However, pruning of excitatory synapses has only been shown on pyramidal neurons despite the well-recognized role of parvalbumin (PV) interneurons in working memory. Moreover, in schizophrenia, working memory deficits are thought to result from disturbances in the maturation of PV interneurons. Here we demonstrate in the monkey prefrontal cortex that excitatory synapses on PV interneurons are pruned across adolescence, the remaining synapses are strengthened, and splicing of erb-b2 receptor tyrosine kinase 4 (ErbB4) may mediate these effects. These findings provide a developmental context for deficient excitatory synaptic inputs to PV interneurons in schizophrenia and implicate dysregulated ErbB4 splicing as a potential molecular mechanism underlying this process. Working memory requires efficient excitatory drive to parvalbumin-positive (PV) interneurons in the primate dorsolateral prefrontal cortex (DLPFC). Developmental pruning eliminates superfluous excitatory inputs, suggesting that working memory maturation during adolescence requires pruning of excitatory inputs to PV interneurons. Therefore, we tested the hypothesis that excitatory synapses on PV interneurons are pruned during adolescence. The density of excitatory synapses, defined by overlapping vesicular glutamate transporter 1-positive (VGlut1+) and postsynaptic density 95-positive (PSD95+) puncta, on PV interneurons was lower in postpubertal relative to prepubertal monkeys. In contrast, puncta levels of VGlut1 and PSD95 proteins were higher in postpubertal monkeys and positively predicted activity-dependent PV levels, suggesting a greater strength of the remaining synapses after pruning. Because excitatory synapse number on PV interneurons is regulated by erb-b2 receptor tyrosine kinase 4 (ErbB4), whose function is influenced by alternative splicing, we tested the hypothesis that pruning of excitatory synapses on PV interneurons is associated with developmental shifts in ErbB4 expression and/or splicing. Pan-ErbB4 expression did not change, whereas the minor-to-major splice variant ratios increased with age. In cell culture, the major, but not the minor, variant increased excitatory synapse number on PV interneurons and displayed greater kinase activity than the minor variant, suggesting that the effect of ErbB4 signaling in PV interneurons is mediated by alternative splicing. Supporting this interpretation, in monkey DLPFC, higher minor-to-major variant ratios predicted lower PSD95+ puncta density on PV interneurons. Together, our findings suggest that ErbB4 splicing may regulate the pruning of excitatory synapses on PV interneurons during adolescence.
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