Chemokine receptors and cortical interneuron dysfunction in schizophrenia

Abstract

Alterations in inhibitory (GABA) neurons, including deficiencies in the GABA synthesizing enzyme GAD67, in the prefrontal cortex in schizophrenia are pronounced in the subpopulations of neurons that contain the calcium-binding protein parvalbumin or the neuropeptide somatostatin. The presence of similar illness-related deficits in the transcription factor Lhx6, which regulates prenatal development of parvalbumin and somatostatin neurons, suggests that cortical GABA neuron dysfunction may be related to disturbances in utero. Since the chemokine receptors CXCR4 and CXCR7 guide the migration of cortical parvalbumin and somatostatin neurons from their birthplace in the medial ganglionic eminence to their final destination in the neocortex, we sought to determine whether altered CXCR4 and/or CXCR7 mRNA levels were associated with disturbances in GABA-related markers in schizophrenia. Quantitative PCR was used to quantify CXCR4 and CXCR7 mRNA levels in the prefrontal cortex of 62 schizophrenia and 62 healthy comparison subjects that were previously characterized for markers of parvalbumin and somatostatin neurons and in antipsychotic-exposed monkeys. We found elevated mRNA levels for CXCR7 (+ 29%; p < .0001) and CXCR4 (+ 14%, p = .052) in schizophrenia subjects but not in antipsychotic-exposed monkeys. CXCR7 mRNA levels were inversely correlated with mRNA levels for GAD67, parvalbumin, somatostatin, and Lhx6 in schizophrenia but not in healthy subjects. These findings suggest that higher mRNA levels for CXCR7, and possibly CXCR4, may represent a compensatory mechanism to sustain the migration and correct positioning of cortical parvalbumin and somatostatin neurons in the face of other insults that disrupt the prenatal development of cortical GABA neurons in schizophrenia.

Introduction

Alterations in inhibitory (GABA) neurons in the prefrontal cortex in schizophrenia, including lower transcript levels for the GABA synthesizing enzyme glutamate decarboxylase (GAD67) (Akbarian et al., 1995, Guidotti et al., 2000, Volk et al., 2000, Volk et al., 2014, Straub et al., 2007, Duncan et al., 2010, Curley et al., 2011, Kimoto et al., 2014), are among the most consistently reported postmortem findings in schizophrenia. Specific subpopulations of GABA neurons, in particular those that contain the calcium-binding protein parvalbumin or the neuropeptide somatostatin, have been reported to be severely affected in the illness (Hashimoto et al., 2003, Morris et al., 2008, Mellios et al., 2009, Fung et al., 2010, Volk et al., 2012, Glausier et al., 2014). Recent evidence suggests that the disease process that leads to dysfunction of cortical parvalbumin and somatostatin neurons may have a prenatal origin. For example, approximately 50% of parvalbumin neurons have been reported to fail to complete their phenotypic specification into fully functioning GABA neurons (Hashimoto et al., 2003), while disrupted migration of cortical somatostatin neurons has also been reported (Yang et al., 2011). Furthermore, we recently reported disease-related deficits in the transcription factor Lhx6 (Volk et al., 2012, Volk et al., 2014), which is important for the prenatal development of cortical parvalbumin and somatostatin neurons as they tangentially migrate out of the medial ganglionic eminence and toward the cerebral cortex (Liodis et al., 2007, Zhao et al., 2008, Neves et al., 2013, Vogt et al., 2014). However, subsequent animal models revealed that a partial loss of Lhx6 similar to that seen in schizophrenia was not sufficient in isolation to reproduce the pattern of disturbances in cortical GABA neurons seen in schizophrenia (Neves et al., 2013, Volk et al., 2014). These findings indicate the need to explore whether additional factors that regulate the prenatal ontogeny of cortical GABA neurons may also be altered in schizophrenia and perhaps may interact with deficits in Lhx6 to produce GABA-related disturbances similar to those seen in schizophrenia.

Interestingly, the chemotaxic cytokine (i.e. chemokine) receptors CXCR4 and CXCR7, which bind the ligand CXCL12 (also known as stromal cell-derived factor-1; SDF-1) (Balabanian et al., 2005), are expressed by migrating cortical interneurons, including future cortical parvalbumin and somatostatin neurons (Stumm et al., 2003, Stumm et al., 2007, Li et al., 2008, Lopez-Bendito et al., 2008, Tanaka et al., 2010, Sanchez-Alcaniz et al., 2011, Wang et al., 2011). CXCR4 and CXCR7 play critical roles in sustaining the tangential migration of cortical parvalbumin and somatostatin neurons from their birth in the medial ganglionic eminence to their final destination in the neocortex, including the timing of their radial migration through the cortical plate (Li et al., 2008, Tanaka et al., 2010, Sanchez-Alcaniz et al., 2011, Wang et al., 2011, Vogt et al., 2014). Furthermore, Lhx6 can affect the expression of CXCR7 by binding to an intronic enhancer element of CXCR7, while transduction of CXCR7 can, in turn, partially compensate for the deleterious effects of a loss of Lhx6 on cortical GABA neuron migration (Vogt et al., 2014). These findings raise the question of whether alterations in CXCR4 and/or CXCR7 in the prefrontal cortex in schizophrenia may act in concert with, or may instead compensate for, deficits in Lhx6 to affect prenatal ontogeny of cortical parvalbumin and somatostatin neurons in schizophrenia.