Joëlle Lavoie

The Electroretinogram as a Biomarker of Central Dopamine and Serotonin: Potential Relevance to Psychiatric Disorders

BACKGROUND Dysfunctions in brain dopamine and serotonin neurotransmission are believed to be involved in the etiology of psychiatric disorders, and electroretinogram (ERG) anomalies have been reported in psychiatric patients. The goal of this study was to evaluate whether ERG anomalies could result from central dopamine or serotonin dysfunctions or from changes in the retinal bioavailability of these neurotransmitters. METHOD Photopic and scotopic ERGs were recorded in R439H tryptophan hydroxylase 2 knockin (Tph2-KI) mice that have an approximately 80% decrease in brain serotonin and dopamine transporter knockout (DAT-KO) mice showing a fivefold increase in brain extracellular dopamine. Dopamine and serotonin retinal and striatal tissue content were also measured. The role of dopamine D1 receptors (D1R) and D2 receptors (D2R) in the ERG responses was evaluated in D1R-KO and D2R-KO mice. RESULTS An increase in photopic b-wave implicit time was observed in Tph2-KI mice (wildtype = 24.25 msec, KI = 25.22 msec; p = .011). The DAT-KO mice showed a decrease in rod sensitivity (wildtype =-1.97 log units, KO =-1.81 log units; p = .014). In contrast to remarkable alterations in brain levels, no changes in dopamine and serotonin retinal content were found in DAT-KO and Tph2-KI mice, respectively. The D1R-KO mice showed anomalies in photopic and scotopic maximal amplitude, whereas D2R-KO mice showed higher oscillatory potentials relative contribution to the b-wave amplitude. CONCLUSION Alterations in central dopamine and serotonin neurotransmission can affect the ERG responses. The ERG anomalies reported in psychiatric disorders might serve as biomarkers of central monoaminergic dysfunction, thus promoting ERG measurements as a useful tool in psychiatric research.

The brain through the retina: the flash electroretinogram as a tool to investigate psychiatric disorders.

Investigating the living brain remains one of the major obstacles in psychiatry research in order to better understand the biological underpinning of brain disorders. Novel approaches are needed to study brain functions indirectly. Since it is part of the central nervous system, retinal functions as measured with the flash electroretinogram (ERG) may reflect the central dysfunctions reported in psychiatric disorders. This review describes the flash ERG anomalies reported in patients with psychiatric disorders such as seasonal affective disorder, schizophrenia, autism spectrum disorder and drug addiction and discusses how changes in retinal functions might be used as biomarkers for psychiatric disorder as well as a potential aid to diagnosis in psychiatry.

Glycogen synthase kinase-3β haploinsufficiency lengthens the circadian locomotor activity period in mice.

The mood stabiliser drug lithium has been reported to impact circadian rhythms in vertebrates. Among several putative therapeutic molecular targets, direct inhibition of glycogen synthase kinase-3 beta (GSK3β) by lithium has been proposed to underlie its effects on circadian physiology. Here we study the effect of GSK3β haploinsufficiency on the circadian locomotor activity in mice during a free-running period in comparison to wildtype littermates (WT). Mice were housed individually to record their circadian wheel running activity and were entrained to a 12h light/12h dark cycle for 14 days and then placed under constant darkness for 14 days to allow free-running. During the free-running phase, the circadian locomotor activity period of GSK3β(+/-) was significantly lengthened (23.83±0.05h) when compared to the WT mice (23.54±0.10h; p=0.0374). No significant difference in locomotor activity was observed. Knowing that GSK3β interacts with most of the core clock components, these data suggest that GSK3β acts as a critical intrinsic regulator of the circadian clock and plays an important role in regulating its period in response to lithium treatment.

The Olfactory Neural Epithelium As a Tool in Neuroscience

Capturing both dynamic changes (state) and persistent signatures (trait) directly associated with disease at the molecular level is crucial in modern medicine. The olfactory neural epithelium, easily accessible in clinical settings, is a promising surrogate model in translational brain medicine, complementing the limitations in current engineered cell models.

Glycogen synthase kinase-3 overexpression replicates electroretinogram anomalies of offspring at high genetic risk for schizophrenia and bipolar disorder.

BACKGROUND Electroretinogram (ERG) anomalies occur in patients with psychiatric disorders and represent potential biomarkers for diagnosis. For instance, decreased rod ERG (b-wave amplitude at Vmax) is a biological endophenotype in young offspring at high genetic risk (HR) for schizophrenia (SZ) and bipolar disorder (BD). Also, a decrease in cone a-wave and rod a- and b- wave was observed in SZ patients. However, the biological underpinning of these anomalies remains unknown. Several genetic variants associated with enhanced risk for SZ and/or BD can activate glycogen synthase kinase-3 isozymes (GSK3α and β). Here we examined the potential contribution of GSK3α and β in the modulation of the ERG. METHODS Cone and rod ERGs were recorded in mice having increased (prpGSK3β mice) or reduced (GSK3β(+/-) mice) GSK3β expression and in GSK3α knockout (KO) mice. RESULTS In prpGSK3β mice, we observed a decrease in rod b-wave amplitude at Vmax, whereas enhanced b-wave amplitude at Vmax was found in GSK3β(+/-) mice. An increase in cone a- and b-wave amplitude at Vmax and in rod b-wave amplitude at Vmax was observed in GSK3α-KO mice. CONCLUSIONS GSK3 expression modulates some ERG parameters. The phenotype observed in prpGSK3β mice is consistent with observations made in HRs. ERG anomalies observed in GSK3β(+/-) and GSK3α-KO mice confirm an association between the rod and cone b-wave amplitude and the expression of GSK3 isozymes. Changes in GSK3 expression or activity may explain some ERG anomalies in HRs and patients, thus supporting the biological validity of ERG measurements as a valuable biomarker for psychiatric research.

The emerging field of retinal electrophysiological measurements in psychiatric research: A review of the findings and the perspectives in major depressive disorder

Major depressive disorder (MDD) is a severe mental illness leading to long-term disabilities. One of the current challenges in psychiatric research is to develop new approaches to investigate the pathophysiology of MDD and monitor drug response in order to provide better therapeutic strategies to the patients. Since the retina is considered as part of the central nervous system, it was suggested that it constitutes an appropriate site to investigate mental illnesses. In the past years, several teams assessed the retinal function of patients with mood disorders and many relevant abnormalities have been reported. Investigation of the retinal electrophysiological abnormalities in MDD remains a young emerging field, but we believe that the current findings are very promising and we argue that objective retinal electrophysiological measurements may eventually become relevant tools to investigate the pathophysiology of MDD. Here, we review the retinal abnormalities detected with objective electrophysiological measurements such as the flash electroretinogram (fERG), the pattern electroretinogram (PERG) and the electrooculogram (EOG) in patients with MDD. We discuss how these changes might reflect the pathophysiology of MDD in both clinical and scientific points of view, according especially to the monoamine neurotransmission deficiency hypothesis. We also discuss the technical details that must be taken into consideration for a potential use of the objective retinal electrophysiological measurements as tools to investigate the pathophysiology of MDD.

Loss of Bmi1 causes anomalies in retinal development and degeneration of cone photoreceptors.

ABSTRACT Retinal development occurs through the sequential but overlapping generation of six types of neuronal cells and one glial cell type. Of these, rod and cone photoreceptors represent the functional unit of light detection and phototransduction and are frequently affected in retinal degenerative diseases. During mouse development, the Polycomb group protein Bmi1 is expressed in immature retinal progenitors and differentiated retinal neurons, including cones. We show here that Bmi1 is required to prevent post natal degeneration of cone photoreceptors and bipolar neurons and that inactivation of Chk2 or p53 could improve but not overcome cone degeneration in Bmi1−/− mice. The retinal phenotype of Bmi1−/− mice was also characterized by loss of heterochromatin, activation of tandem repeats, oxidative stress and Rip3-associated necroptosis. In the human retina, BMI1 was preferentially expressed in cones at heterochromatic foci. BMI1 inactivation in human embryonic stem cells was compatible with retinal induction but impaired cone terminal differentiation. Despite this developmental arrest, BMI1-deficient cones recapitulated several anomalies observed in Bmi1−/− photoreceptors, such as loss of heterochromatin, activation of tandem repeats and induction of p53, revealing partly conserved biological functions between mouse and man. Summary: Bmi1 is required to prevent postnatal degeneration of cone photoreceptors and bipolar neurons, while BMI1 inactivation in human embryonic stem cells impairs cone terminal differentiation.

Negative impact of melatonin ingestion on the photopic electroretinogram of dogs

Melatonin follows a circadian rhythm entrained by the light/dark cycle and plays a role in promoting light sensitivity at night. It has been suggested that melatonin and dopamine reciprocal inhibition may contribute to the switch between day and night vision. The purpose of this study was to investigate the impact of a high dose of melatonin administration on the photopic and scotopic electroretinogram (ERG) of dogs in the daytime, when it is not thought to be present. Photopic and scotopic ERG luminance response functions were obtained from 7 anaesthetized beagle dogs (3 males and 4 females), once without melatonin (control) and once after oral administration of melatonin (90 mg/dog). Vmax (maximal b-wave amplitude achieved) and logK (retinal sensitivity) were calculated from the derived luminance response function. Photopic flicker ERG was also recorded. In photopic condition, a-wave amplitude (control: -126.90 μV; with melatonin: -49.64 μV; p<0.001) and Vmax (control: 252.50 μV; with melatonin: 115.40 μV; p<0.001) were decreased. A significant reduction of the photopic flicker ERG amplitude was observed after melatonin ingestion. In scotopic condition, an overall difference was reported before and after melatonin ingestion for the a- and b-wave amplitude, but no change was significant for Vmax. Melatonin ingestion at a high dose during the day decreases the photopic amplitude of a- and b-wave, but has no impact on implicit time. This negative impact of melatonin on photopic system may serve to promote night vision.