Prefrontal Cortex-based Schizophrenia Phenotypes Linked to Variation in Williams Syndrome Gene LIMK1

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Abstract Submission 

Shane Kippenhan¹, Michael Gregory¹, Daniel Eisenberg¹, Tiffany Nash¹, Carolyn Mervis², Bhaskar Kolachana¹, Destiny Wright¹, Madeline Garvey¹, Philip Kohn¹, Karen Berman¹

¹NIMH, National Institutes of Health, Bethesda, MD, ²University of Louisville, Louisville, KY

Shane Kippenhan  
NIMH, National Institutes of Health
Bethesda, MD

Michael Gregory  
NIMH, National Institutes of Health
Bethesda, MD

Daniel Eisenberg  
NIMH, National Institutes of Health
Bethesda, MD

Tiffany Nash  
NIMH, National Institutes of Health
Bethesda, MD

Carolyn Mervis  
University of Louisville
Louisville, KY

Bhaskar Kolachana  
NIMH, National Institutes of Health
Bethesda, MD

Destiny Wright  
NIMH, National Institutes of Health
Bethesda, MD

Madeline Garvey  
NIMH, National Institutes of Health
Bethesda, MD

Philip Kohn  
NIMH, National Institutes of Health
Bethesda, MD

Karen Berman  
NIMH, National Institutes of Health
Bethesda, MD

LIMK1, one of ~26 genes hemideleted in Williams syndrome (WS), is vital to the neural processes of axonal migration, synaptic plasticity, and the regulation of dendritic spines, all of which critically depend on LIMK1's role in modulating cofilin and actin polymerization(1). In WS, this gene has been associated with structural and functional alterations of the inferior parietal sulcus(2), but recent work suggests that LIMK1 may also be important in pathophysiologies of other neuropsychiatric conditions, including schizophrenia, which is associated with dorsolateral prefrontal cortex (DLPFC) dysfunction(3,4). For example, a study of post-mortem DLPFC samples from individuals with schizophrenia found increased expression of LIMK1 as well as decreased dendritic spine density in cortical layer 3(5). Additionally, in mouse models of schizophrenia, schizophrenia-like behaviors and spine alterations were both rescued by LIMK1 inhibition(6). Here, we tested whether variations in LIMK1 expression were related to DLPFC structure and function – leveraging naturally occurring expression differences that are present in individuals with rare 7q11.23 copy number variations (CNVs) as well as in the general population, wherein differences are present as a function of LIMK1 haplotype. In each case, we tested whether LIMK1 variation was associated with structural or functional DLPFC changes that were consistent with known schizophrenia phenotypes.

We first studied regional gray-matter volume (GMV) with respect to 7q11.23 copy number in three groups: (1) children and adolescents with WS (having only one copy of LIMK1 and, thus, reduced LIMK1 expression; N=30, 79 longitudinal visits, mean age=12.8±3.2 years, 20 females), (2) typically developing (TD) individuals (with two copies of LIMK1; N=94, 288 visits, age=12.8±3.2 years, 47 females), and (3) children and adolescents with 7q11.23 Duplication syndrome ([Dup7]; with three copies of LIMK1 and increased LIMK1 expression; N=16, 35 visits, age=14.1±3.1 years, 9 females). We also performed a similarly structured copy number-based fMRI study of a spatial working memory task (again testing across WS, TD, and Dup7 groups). Finally, we examined the relationship between GMV and LIMK1 expression in two separate samples of healthy participants from the general population, one sample from NIMH (255 participants, age=33.0±9.7 years, 142 females), and another from the Human Connectome Project (216 participants, age = 29.3±3.7 years, 140 females). Each of these two general population cohorts was stratified according to a LIMK1 haplotype that has been shown to robustly predict imputed LIMK1 expression in the cerebral cortex(2).

In the copy number-based structural study, there was an association between DLPFC GMV and LIMK1 copy number (and, thus, gene expression) that was consistent with the previously reported schizophrenia-based phenotype: lower DLPFC GMV was associated with increasing LIMK1 copy number (i.e., higher expression; p<0.001). In the fMRI study, we found an association between LIMK1 copy number and working memory-related activation that was also consistent with the schizophrenia phenotype: reduced DLPFC activation was related to increased copy number/LIMK1 expression (p<0.001). Finally, in each of the two general population cohorts stratified by LIMK1 haplotype, we found reduced DLPFC GMV in the haplotype group linked to higher LIMK1 expression (p<0.005 in both discovery and replication cohorts).

Here, we provide in vivo evidence in humans that LIMK1 function is relevant to hallmark schizophrenia brain phenotypes in the DLPFC, including reduced gray matter volume and working memory hypoactivation. Given prior preclinical studies showing that normalization of LIMK1 activity can enhance dendritic spine density and improve neural function, these findings may have implications for understanding mechanisms of pathology in neuropsychiatric disorders, perhaps even for future therapeutic approaches.

Neurodevelopmental/ Early Life (eg. ADHD, autism)

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ¹

Working Memory

Lifespan Development Other ²

Cortex

Cortical Layers

Development

DISORDERS

FUNCTIONAL MRI

Morphometrics

MRI

Psychiatric Disorders

Schizophrenia

STRUCTURAL MRI