Key cognitive abilities depend, in part, on gamma oscillations generated by the synchronization of the activity of excitatory pyramidal neurons (PNs) by inhibition from parvalbumin (PV)-containing basket cells (PVBCs) that are reciprocally-connected in a microcircuit in layer 3 (L3) of the dorsolateral prefrontal cortex (PFC). Thus, core cognitive impairments in schizophrenia (SZ) are thought to reflect alterations in L3PNs that produce compensatory changes in PVBCs. In L3PNs, these abnormalities include 1) altered expression of genes regulating the actin dynamics that supports cell morphology, 2) smaller somal size and fewer dendritic spines (the main site of excitatory inputs to PNs), 3) downregulated activity-dependent markers and 4) reduced markers of energy production. These findings raise key questions that can only be answered by conducting studies at the level of single L3PNs. First, are altered actin regulation, smaller somal size, and lower markers of activity and energy production co-localized within and correlated across L3PNs in SZ (Aim 1)? Co- localized alterations in some L3PNs would support the few studies of single measures in individual L3PNs which suggest that only a subset of L3PNs are affected in SZ. Correlated alterations across neurons would support a causal pathway intrinsic to L3PNs in which altered actin regulation produces morphological abnormalities that result in fewer excitatory inputs to the affected L3PNs, reducing their activity and the requirement for energy production. Second, do the affected L3PNs display compensatory downregulation of inhibitory synaptic strength at their PVBC inputs (Aim 2)? An affirmative answer would support the idea that disturbances intrinsic to L3PNs are upstream of alterations in PVBCs given that lower L3PN activity is thought to induce reductions in inhibition via synaptic homeostasis mechanisms. Third, do reductions in L3PN activity induce lower inhibitory synaptic strength in the L3PN-PVBC microcircuit of adult monkey PFC (Aim 3)? Such synaptic homeostasis occurs in sensory cortices of immature rodents, but has not been studied in the adult primate PFC, which has multiple distinctive synaptic and connectivity properties. Experimental evidence of this homeostatic mechanism in the mature primate PFC would support the idea that PVBCs display compensatory responses downstream of lower L3PN activity. Fourth, does the magnitude of alterations in affected PFC L3PNs predict indices of cognition across diagnoses (Aim 4)? An affirmative answer would support the idea that L3PN- PVBC microcircuit alterations contribute to the neural substrate for cognitive deficits in SZ. The proposed studies will answer these questions by 1) quantitative, single cell analyses of the PFC L3 PN-PVBC microcircuit at levels of resolution that are unique in postmortem human studies, 2) proof-of-concept experimental tests of key microcircuit functional properties in monkeys, and 3) a direct comparison of microcircuit and cognitive measures in the same subjects. The results will provide novel insights into the neural substrate of cognitive dysfunction in SZ and into potential targets for innovative therapeutic interventions.

Public Health Relevance

Key cognitive abilities depend, in part, on gamma oscillations generated by the synchronization of the activity of excitatory pyramidal neurons by inhibition from parvalbumin-containing basket cells that are reciprocally- connected in a microcircuit in layer 3 of the dorsolateral prefrontal cortex. Thus, core cognitive impairments in schizophrenia are thought to reflect alterations in layer 3 pyramidal neurons that induce compensatory changes in parvalbumin-containing basket cells. The proposed studies will test this hypothesis at the level of single neurons and the results will provide novel insights into the neural substrate of cognitive dysfunction in schizophrenia and into potential targets for innovative therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH043784-27
Application #
9657498
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Meinecke, Douglas L
Project Start
1988-09-30
Project End
2023-11-30
Budget Start
2019-02-15
Budget End
2019-11-30
Support Year
27
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Dienel, Samuel J; Lewis, David A (2018) Alterations in cortical interneurons and cognitive function in schizophrenia. Neurobiol Dis :
Glausier, Jill R; Lewis, David A (2017) GABA and schizophrenia: Where we stand and where we need to go. Schizophr Res 181:2-3
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Glausier, Jill R; Roberts, Rosalinda C; Lewis, David A (2017) Ultrastructural analysis of parvalbumin synapses in human dorsolateral prefrontal cortex. J Comp Neurol 525:2075-2089
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

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