Structural and functional consequences of PAX6 mutations in the brain: Implications for aniridia.

The paired-box 6 (PAX6) gene encodes a highly conserved transcription factor essential for the proper development of the eye and brain. Heterozygous loss-of-function mutations in PAX6 are causal for a condition known as aniridia in humans and the Small eye phenotype in mice. Aniridia is characterized by iris hypoplasia and other ocular abnormalities, but recent evidence of neuroanatomical, sensory, and cognitive impairments in this population has emerged, indicating brain-related phenotypes as a prevalent feature of the disorder. Determining the neurophysiological origins of brain-related phenotypes in this disorder presents a substantial challenge, as the majority of extra-ocular traits in aniridia demonstrate a high degree of heterogeneity. Here, we summarize and integrate findings from human and rodent model studies, which have focused on neuroanatomical and functional consequences of PAX6 mutations. We highlight novel findings from PAX6 central nervous system studies in adult mammals, and integrate these findings into what we know about PAX6's role in development of the central nervous system. This review presents the current literature in the field in order to inform clinical application, discusses what is needed in future studies, and highlights PAX6 as a lens through which to understand genetic disorders affecting the human nervous system.

Global and age-related neuroanatomical abnormalities in a Pax6-deficient mouse model of aniridia suggests a role for Pax6 in adult structural neuroplasticity.

PAX6 encodes a highly conserved transcription factor necessary for normal development of the eyes and central nervous system. Heterozygous loss-of-function mutations in PAX6 cause the disorder aniridia in humans and the Small eye trait in mice. Aniridia is a congenital and progressive disorder known for ocular phenotypes; however, recently, consequences of PAX6 haploinsufficiency in the brains of aniridia patients have been identified. These findings span structural and functional abnormalities, including deficits in cognitive and sensory processing. Furthermore, some of these abnormalities are accelerated as aniridia patients age. Although some functional abnormalities may be explained by structural changes, variability of results remain, and the effects of PAX6 heterozygous loss-of-function mutations on neuroanatomy, particularly with regard to aging, have yet to be resolved. Our study used high-resolution magnetic resonance imaging (MRI) and histology to investigate structural consequences of such mutations in the adult brain of our aniridia mouse model, Small eye Neuherberg allele (Pax6SeyNeu/+), at two adult age groups. Using both MRI and histology enables a direct comparison with human studies, while providing higher resolution for detection of more subtle changes. We show volumetric changes in major brain regions of the the Pax6SeyNeu/+ mouse compared to wild-type including genotype- and age-related olfactory bulb differences, age-related cerebellum differences, and genotype-related eye differences. We also show alterations in thickness of major interhemispheric commissures, particularly those anteriorly located within the brain including the optic chiasm, corpus callosum, and anterior commissure. Together, these genotype and age related changes to brain volumes and structures suggest a global decrease in adult brain structural plasticity in our Pax6SeyNeu/+ mice.

Molecular alterations in the medial temporal lobe in schizophrenia.

The medial temporal lobe (MTL) and its individual structures have been extensively implicated in schizophrenia pathophysiology, with considerable efforts aimed at identifying structural and functional differences in this brain region. The major structures of the MTL for which prominent differences have been revealed include the hippocampus, the amygdala and the superior temporal gyrus (STG). The different functions of each of these regions have been comprehensively characterized, and likely contribute differently to schizophrenia. While neuroimaging studies provide an essential framework for understanding the role of these MTL structures in various aspects of the disease, ongoing efforts have sought to employ molecular measurements in order to elucidate the biology underlying these macroscopic differences. This review provides a summary of the molecular findings in three major MTL structures, and discusses convergent findings in cellular architecture and inter-and intra-cellular networks. The findings of this effort have uncovered cell-type, network and gene-level specificity largely unique to each brain region, indicating distinct molecular origins of disease etiology. Future studies should test the functional implications of these molecular changes at the circuit level, and leverage new advances in sequencing technology to further refine our understanding of the differential contribution of MTL structures to schizophrenia.

Early and late auditory information processing show opposing deviations in aniridia.

Aniridia is a congenital disorder, predominantly caused by heterozygous mutations of the PAX6 gene. While ocular defects have been extensively characterized in this population, brain-related anatomical and functional abnormalities are emerging as a prominent feature of the disorder. Individuals with aniridia frequently exhibit auditory processing deficits despite normal audiograms. While previous studies have reported hypoplasia of the anterior commissure and corpus callosum in some of these individuals, the neurophysiological basis of these impairments remains unexplored. This study provides direct assessment of neural activity related to auditory processing in aniridia. Participants were presented with tones designed to elicit an auditory steady-state response (ASSR) at 22 Hz, 40 Hz, and 84 Hz, and infrequent broadband target tones to maintain attention during electroencephalography (EEG) recording. Persons with aniridia showed increased early cortical responses (P50 AEP) in response to all tones, and increased high-frequency oscillatory entrainment (84 Hz ASSR). In contrast, this group showed a decreased cortical integration response (P300 AEP to target tones) and reduced neural entrainment to cortical beta-band stimuli (22 Hz ASSR). Collectively, our results suggest that subcortical and early cortical auditory processing is augmented in aniridia, while functional cortical integration of auditory information is deficient in this population.

Microstructural differences in visual white matter tracts in people with aniridia.

Aniridia is a panocular disorder characterized chiefly by iris hypoplasia. Most cases result from mutations of the PAX6 gene, which is important in both eye and brain development. In addition to ocular alterations, differences in global brain volume and functional connectivity have been reported in humans with aniridia. Understanding neural alterations in aniridia may require examination of possible differences in white matter structure, as few studies have assessed white matter in this population. The current study utilized diffusion-weighted imaging to assess white matter structure in 11 people with aniridia and 11 healthy comparison participants, matched for sex and age. A map of the local connectome was calculated to compare quantitative anisotropy (QA), an index of white matter tract density, in all white matter voxels, revealing subcomponents of white matter tracts with differing QA between people with aniridia and healthy comparisons. The analysis indicated that QA was lower for people with aniridia in portions of bilateral optic tract [t(20)=-4.23, P=0.001, d=-1.80], bilateral optic radiation [t(20)=-4.06, P=0.001, d=-1.73], forceps major [t(20)=-3.65, P=0.002, d=-1.55], bilateral superior longitudinal fasciculus [left: t(20)=-3.15, P=0.005, d=-1.34; right, t(20)=-4.28, P<0.001, d=-1.83], and right posterior corona radiata [t(20)=-3.19, P=0.006, d=-1.36]. These differences demonstrate that white matter structure is altered in people with aniridia in both visual tracts and associated posterior visual pathways.

Structural brain abnormalities in 12 persons with aniridia.

Background: Aniridia is a disorder predominately caused by heterozygous loss-of-function mutations of the PAX6 gene, which is a transcriptional regulator necessary for normal eye and brain development.  The ocular abnormalities of aniridia have been well characterized, but mounting evidence has implicated brain-related phenotypes as a prominent feature of this disorder as well.  Investigations using neuroimaging in aniridia patients have shown reductions in discrete brain structures and changes in global grey and white matter.  However, limited sample sizes and substantive heterogeneity of structural phenotypes in the brain remain a challenge.  Methods: Here, we examined brain structure in a new population sample in an effort to add to the collective understanding of anatomical abnormalities in aniridia.  The current study used 3T magnetic resonance imaging to acquire high-resolution structural data in 12 persons with aniridia and 12 healthy demographically matched comparison subjects.  Results: We examined five major structures: the anterior commissure, the posterior commissure, the pineal gland, the corpus callosum, and the optic chiasm.  The most consistent reductions were found in the anterior commissure and the pineal gland; however, abnormalities in all of other structures examined were present in at least one individual.  Conclusions: Our results indicate that the anatomical abnormalities in aniridia are variable and largely individual-specific.  These findings suggest that future studies investigate this heterogeneity further, and that normal population variation should be considered when evaluating structural abnormalities.

Stimulus train duration but not attention moderates γ-band entrainment abnormalities in schizophrenia.

Electroencephalographic (EEG) studies of auditory steady-state responses (aSSRs) non-invasively probe gamma-band (40-Hz) oscillatory capacity in sensory cortex with high signal-to-noise ratio. Consistent reports of reduced 40-Hz aSSRs in persons with schizophrenia (SZ) indicate its potential as an efficient biomarker for the disease, but studies have been limited to passive or indirect listening contexts with stereotypically short (500ms) stimulus trains. An inability to modulate sensorineural processing in accord with behavioral goals or within the sensory environmental context may represent a fundamental deficit in SZ, but whether and how this deficit relates to reduced aSSRs is unknown. We systematically varied stimulus duration and attentional contexts to further mature the 40-Hz aSSR as biomarker for future translational or mechanistic studies. Eighteen SZ and 18 healthy subjects (H) were presented binaural pure-tones with or without sinusoidal amplitude modulation at 40-Hz. Stimulus duration (500-ms or 1500-ms) and attention (via a button press task) were varied across 4 separate blocks. Evoked potentials recorded with dense-array EEGs were analyzed in the time-frequency domain. SZ displayed reduced 40-Hz aSSRs to typical stimulation parameters, replicating previous findings. In H, aSSRs were reduced when stimuli were presented in longer trains and were slightly enhanced by attention. Only the former modulation was impaired in SZ and correlated with sensory discrimination performance. Thus, gamma-band aSSRs are modulated by both attentional and stimulus duration contexts, but only modulations related to physical stimulus properties are abnormal in SZ, supporting its status as a biomarker of psychotic perceptual disturbance involving non-attentional sensori-cortical circuits.

Increased functional connectivity in intrinsic neural networks in individuals with aniridia.

Mutations affecting the PAX6 gene result in aniridia, a condition characterized by the lack of an iris and other panocular defects. Among humans with aniridia, structural abnormalities also have been reported within the brain. The current study examined the functional implications of these deficits through "resting state" or task-free functional magnetic resonance imaging (fMRI) in 12 individuals with aniridia and 12 healthy age- and gender-matched controls. Using independent components analysis (ICA) and dual regression, individual patterns of functional connectivity associated with three intrinsic connectivity networks (ICNs; executive control, primary visual, and default mode) were compared across groups. In all three analyses, the aniridia group exhibited regions of greater connectivity correlated with the network, while the controls did not show any such regions. These differences suggest that individuals with aniridia recruit additional neural regions to supplement function in critical intrinsic networks, possibly due to inherent structural or sensory abnormalities related to the disorder.