title: Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex.
abstract: 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.
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213.|Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Chung
authors.affiliation: Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Wills
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Fish
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213; lewisda@upmc.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D005260:Female; D007395:Interneurons / Q000502:physiology*; D008253:Macaca mulatta; D008570:Memory, Short-Term / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D010320:Parvalbumins / Q000502:physiology*; D017397:Prefrontal Cortex / Q000502:physiology*; D020033:Protein Isoforms; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000502:physiology*
chemical_list: D010320:Parvalbumins; D020033:Protein Isoforms; D066247:Receptor, ErbB-4
keywords: ErbB4; alternative splicing; parvalbumin interneuron; schizophrenia; synaptic pruning