# Prefrontal microcircuitry and cognition in schizophrenia

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $725,456

## Abstract

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...

## Key facts

- **NIH application ID:** 9873986
- **Project number:** 5R01MH043784-28
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** David A Lewis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $725,456
- **Award type:** 5
- **Project period:** 1988-09-30 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873986

## Citation

> US National Institutes of Health, RePORTER application 9873986, Prefrontal microcircuitry and cognition in schizophrenia (5R01MH043784-28). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9873986. Licensed CC0.

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