Cognitive impairments in schizophrenia (SZ) have been linked to dysfunction of inhibitory prefrontal cortex (PFC) circuitry, including parvalbumin (PV) and somatostatin (SST) neurons. We recently found that disturbances in PFC PV&SST neurons are most prominent in a subset (~50%) of SZ subjects identified as a low GABA marker (LGM) molecular phenotype. The etiopathogenesis of PV&SST neuron dysfunction in the LGM SZ subjects may be influenced by genetic liabilities and/or environmental insults that affect neuronal ontogeny. In humans, embryonic PV&SST neurons express developmental regulators (e.g., Lhx6) and cytokine receptors that regulate their specification and migration. We recently found deficits in PFC Lhx6 mRNA levels that were most prominent in the LGM SZ subjects, suggesting that low Lhx6 levels may impair PV&SST neuron development in SZ. In addition, disturbances in the fetal environment, such as elevated cytokine levels due to maternal immune activation (MIA), increase risk for SZ and lower cortical PV levels. These data suggest that prenatal exposure to altered cytokine levels due to MIA may disrupt the development of cytokine receptor-expressing neurons. Since loss of Lhx6 induces deficits in cytokine receptors and MIA lowers Lhx6 levels, the combination of Lhx6 deficits and MIA may severely disrupt PV&SST neuron development. Therefore, we hypothesize that disturbances in PV&SST neurons in SZ subjects with the LGM phenotype reflect the long-lasting consequences of prenatal insults that are fetal (i.e. deficits in developmental regulators such as Lhx6) and/or maternal (i.e. immune activation) in origin. Testing this central hypothesis requires a translational, cross-species approach.
In Aim 1 we will use tissue and cellular measures of mRNA levels of developmental factors and cytokine receptors critical for PFC PV&SST neuron ontogeny and other immune markers in the PFC of SZ and healthy subjects. We hypothesize that SZ subjects with the LGM phenotype show a pattern of low mRNA levels for developmental factors and high mRNA levels for immune markers relative to other SZ and healthy subjects. SZ and bipolar disorder (BP) share features including genetic risk, psychosis, cognitive impairments, and low PFC PV and GAD67 mRNA levels.
In Aim 2 we will investigate whether a shared pathogenetic mechanism may disrupt PV&SST neuron ontogeny by conducting mRNA studies similar to Aim 1 in BP subjects. We hypothesize that the LGM phenotype and deficits in developmental factors are also present in a subset of BP subjects, but at a lower frequency than SZ. Finally, in Aim 3 we will investigate a potential pathogenetic mechanism that may lead to the LGM phenotype by administering poly I:C which induces cytokine response to pregnant wild-type mice (Lhx6+/- male progenitors) and conducting studies of PFC PV&SST neuron developmental regulators and neurophysiology measures in offspring. We hypothesize that deficits in Lhx6 or MIA independently, and their interaction more severely, leads to deficits in adult PV&SST neurons akin to those seen in the LGM phenotype.

Public Health Relevance

These translational, cross-species studies seek to characterize a molecular 'low GABA marker' phenotype that may contribute to certain clinical features that are shared in subsets of subjects across psychiatric disorders (i.e. schizophrenia and bipolar disorder) and then explore a potential underlying pathogenetic mechanism that involves a gene (i.e. deficits in the ontogenetic transcription factor Lhx6) ? environment (i.e. maternal immune activation) interaction. These findings may facilitate the employment of novel diagnostic strategies, such as imaging or genetic tests, to identify patients with the 'low GABA marker' phenotype, guide personalized treatment approaches that target use of GABA agents to the 'low GABA marker' patients who are most likely to experience a maximal benefit, and may inform preventative strategies involving maternal prenatal care to reduce infection rates and potentially reduce risks for developing schizophrenia in at-risk offspring.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH100066-05
Application #
9392196
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2013-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
5
Fiscal Year
2018
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
Datta, Dibyadeep; Arion, Dominique; Roman, Kaitlyn M et al. (2017) Altered Expression of ARP2/3 Complex Signaling Pathway Genes in Prefrontal Layer 3 Pyramidal Cells in Schizophrenia. Am J Psychiatry 174:163-171
Volk, David W (2017) Role of microglia disturbances and immune-related marker abnormalities in cortical circuitry dysfunction in schizophrenia. Neurobiol Dis 99:58-65
Chung, Daniel W; Volk, David W; Arion, Dominique et al. (2016) Dysregulated ErbB4 Splicing in Schizophrenia: Selective Effects on Parvalbumin Expression. Am J Psychiatry 173:60-8
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; Gonzalez-Burgos, Guillermo; Lewis, David A (2016) l-Proline, GABA Synthesis and Gamma Oscillations in Schizophrenia. Trends Neurosci 39:797-798
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
Kimoto, Sohei; Glausier, Jill R; Fish, Kenneth N et al. (2016) Reciprocal Alterations in Regulator of G Protein Signaling 4 and microRNA16 in Schizophrenia. Schizophr Bull 42:396-405
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
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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