The pruning of dendritic spines, and the glutamate synapses they receive, on prefrontal cortex (PFC) layer 3 pyramidal neurons (L3PNs) during adolescence is thought to play a key role in the progression of cognitive dysfunction and the onset of psychosis in schizophrenia. This idea is based, in part, on findings that the densities of L3PN spines and layer 3 axospinous synapses in the primate (but not rodent) PFC decline by ~40% between late childhood and early adulthood, coinciding with the maturation of PFC-mediated cognitive abilities that are impaired in schizophrenia. In monkeys, L3PNs comprise distinct subtypes defined by the cortical projection target of their principal axon. However, prior studies of synaptic pruning in primate PFC did not differentiate between L3PN subtypes, which likely differ in developmental trajectories of synaptic maturation. For example, L3PNs projecting to the ipsilateral parietal cortex (pL3PNs) contribute to the PFC- parietal network mediating cognitive functions that improve substantially across adolescence, when PFC- parietal functional connectivity is enhanced. Thus, synaptic pruning in pL3PNs during adolescence could be critical for the maturation of the PFC-parietal network. In contrast, callosal projection PFC L3PNs (cL3PNs) form the inter-hemispheric network that is refined early and achieves mature features before adolescence. Thus the goal of the proposed studies is to determine the cell type-specificity, functional consequences and molecular correlates of synaptic pruning in the primate PFC during adolescence. In each study, pL3PNs and cL3PNs in monkey PFC are retrogradely-labeled with fluorescent microspheres in vivo, and subjected to in vitro electrophysiology, biocytin filling and confocal imaging or captured by laser microdissection for RNAseq analysis. Using this innovative approach, the following four hypotheses (H) will be tested: H1) Spines on pL3PNs receiving cortical inputs are preferentially pruned during adolescence. In contrast, spines on cL3PNs are not pruned during adolescence. H2) Pruning during adolescence is associated with increases in spine volume and excitatory synaptic current amplitude selectively on pL3PNs. H3) Strengthening of cortical synaptic inputs during adolescence enhances behaviorally-relevant activity of pL3PNs. H4) The transcriptional profiles of pL3PNs and cL3PNs follow distinct developmental trajectories that reflect differences in spine pruning and result in cell type-specific gene expression patterns in the adult PFC that can be used to identify L3PN subtypes in human PFC. Given recent evidence that the genetic liability for schizophrenia alters pruning, the proposed studies will provide critical information to guide the conduct and interpretation of separately-funded studies examining the cell type-specificity and developmental origin of spine deficits in schizophrenia.

Public Health Relevance

In individuals diagnosed with schizophrenia, cognitive deficits tend to worsen and psychotic symptoms tend to first appear during adolescence. The timing of these clinical features is thought to be related to the pruning of excitatory synapses on layer 3 pyramidal neurons in the prefrontal cortex. The proposed studies will determine which pyramidal neurons are normally pruned during adolescence and the functional impact and molecular determinants of pruning in the primate PFC.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1-MDCN-P (57)S)
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Panchision, David M
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University of Pittsburgh
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Pafundo, Diego E; Miyamae, Takeaki; Lewis, David A et al. (2018) Presynaptic Effects of N-Methyl-D-Aspartate Receptors Enhance Parvalbumin Cell-Mediated Inhibition of Pyramidal Cells in Mouse Prefrontal Cortex. Biol Psychiatry 84:460-470
Dienel, Samuel J; Bazmi, Holly H; Lewis, David A (2017) Development of transcripts regulating dendritic spines in layer 3 pyramidal cells of the monkey prefrontal cortex: Implications for the pathogenesis of schizophrenia. Neurobiol Dis 105:132-141
Miyamae, Takeaki; Chen, Kehui; Lewis, David A et al. (2017) Distinct Physiological Maturation of Parvalbumin-Positive Neuron Subtypes in Mouse Prefrontal Cortex. J Neurosci 37:4883-4902
Hoftman, Gil D; Datta, Dibyadeep; Lewis, David A (2017) Layer 3 Excitatory and Inhibitory Circuitry in the Prefrontal Cortex: Developmental Trajectories and Alterations in Schizophrenia. Biol Psychiatry 81:862-873
Volk, D W; Sampson, A R; Zhang, Y et al. (2016) Cortical GABA markers identify a molecular subtype of psychotic and bipolar disorders. Psychol Med 46:2501-12
Volk, David W; Edelson, Jessica R; Lewis, David A (2016) Altered expression of developmental regulators of parvalbumin and somatostatin neurons in the prefrontal cortex in schizophrenia. Schizophr Res 177:3-9
Volk, David W; Lewis, David A (2016) The Role of Endocannabinoid Signaling in Cortical Inhibitory Neuron Dysfunction in Schizophrenia. Biol Psychiatry 79:595-603
Volk, David W; Chitrapu, Anjani; Edelson, Jessica R et al. (2015) Molecular mechanisms and timing of cortical immune activation in schizophrenia. Am J Psychiatry 172:1112-21
Rotaru, Diana C; Olezene, Cameron; Miyamae, Takeaki et al. (2015) Functional properties of GABA synaptic inputs onto GABA neurons in monkey prefrontal cortex. J Neurophysiol 113:1850-61
Volk, David W; Chitrapu, Anjani; Edelson, Jessica R et al. (2015) Chemokine receptors and cortical interneuron dysfunction in schizophrenia. Schizophr Res 167:12-7

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