A series of studies in schizophrenic patients report a decrease of glutathione (GSH) in prefrontal cortex (PFC) and cerebrospinal fluid, a decrease in mRNA levels for two GSH synthesizing enzymes and ...a deficit in parvalbumin (PV) expression in a subclass of GABA neurons in PFC. GSH is an important redox regulator, and its deficit could be responsible for cortical anomalies, particularly in regions rich in dopamine innervation. We tested in an animal model if redox imbalance (GSH deficit and excess extracellular dopamine) during postnatal development would affect PV-expressing neurons. Three populations of interneurons immunolabeled for calcium-binding proteins were analyzed quantitatively in 16-day-old rat brain sections. Treated rats showed specific reduction in parvalbumin immunoreactivity in the anterior cingulate cortex, but not for calbindin and calretinin. These results provide experimental evidence for the critical role of redox regulation in cortical development and validate this animal model used in schizophrenia research.
► Glutathione (GSH) deficit, a risk factor for schizophrenia, can be induced in rats. ► Transitory postnatal GSH reduction impairs cognitive mapping abilities in adults. ► The impairment is ...selectively observed in visually poor environments. ► Compensatory strategies require continuous, specific and complex visual flow. ► Our results correspond to the general binding deficit observed in patients.
Rats were treated postnatally (PND 5–16) with BSO (
l-buthionine-(S,R)-sulfoximine) in an animal model of schizophrenia based on transient glutathione deficit. The BSO treated rats were impaired in patrolling a maze or a homing table when adult, yet demonstrated preserved escape learning, place discrimination and reversal in a water maze task
37. In the present work, BSO rats’ performance in the water maze was assessed in conditions controlling for the available visual cues. First, in a completely curtained environment with two salient controlled cues, BSO rats showed little accuracy compared to control rats. Secondly, pre-trained BSO rats were impaired in reaching the familiar spatial position when curtains partially occluded different portions of the room environment in successive sessions. The apparently preserved place learning in a classical water maze task thus appears to require the stability and the richness of visual landmarks from the surrounding environment. In other words, the accuracy of BSO rats in place and reversal learning is impaired in a minimal cue condition or when the visual panorama changes between trials. However, if the panorama remains rich and stable between trials, BSO rats are equally efficient in reaching a familiar position or in learning a new one. This suggests that the BSO accurate performance in the water maze does not satisfy all the criteria for a cognitive map based navigation on the integration of polymodal cues. It supports the general hypothesis of a binding deficit in BSO rats.
Background:
Besides oxidative stress, evidence indicates the implication of immune dysregulation in schizophrenia. As oxidative stress is known to induce inflammation, we explored the mechanisms ...involved in their interaction using an animal model of redox dysregulation, the GCLM KO mouse, in which a glutathione deficit leads to oxidative stress.
Methods:
In the anterior cingulate cortex (ACC) of GCLM KO mice with or without an additional stress (dopamine uptake inhibitor GBR, P10-P20), we determined oxidative stress (8-oxoDG), microglia markers (Iba1, CD11b and CD68), parvalbumin interneurons (PVI) and perineuronal net (PNN) at both peripuberty (P40) and adulthood (P90). Receptor for Advanced Glycation End-product (RAGE) shedding, and matrix metalloproteinase 9 (MMP9), with and without MMP9 inhibitor, were measured. NFkB activation was measured using an Adeno-Associated Virus (AAV) containing a plasmid, expressing EGFP under the promoter of NFkB responsive element.
Results:
At both peripuberty and adulthood, besides increased oxidative stress marker, microglia activation was increased in GCLM KO ACC. Increased microglia activation was more pronounced at P40 than at P90, revealing a tendency to develop neuroinflammation during youth. In GCLM KO at P40, RAGE shedding was increased in neurons in parallel to an increase of MMP9, suggesting that oxidative stress induced MMP9 activation through a redox switch could be responsible for RAGE shedding: Indeed in vivo inhibition of MMP9 with an siRNA or with a specific inhibitor completely prevented RAGE shedding. Moreover, NFkB activation, which is known to be induced by RAGE, was increased in neurons of GCLM KO, as well as pro-inflammatory cytokines (IL-6, IL-1B and TNFa).
In order to test whether neuroinflammation induced by oxidative stress, following the pathway oxidative stress → MMP9 activation → RAGE shedding → NFKb activation → cytokines induction → microglia activation → reactive oxygen/nitrogen species production → oxidative stress, could be causal to the long lasting PVI/PNN deficit observed in the 2 hits GCLM KO model (±GBR; Cabungcal et al., 2013), the latter was treated with MMP9 inhibitor during puberty (P20-30). MMP9 inhibitor treatment, after the additional oxidative stress insult, reversed PVI/PNN deficit, and reduced oxidative stress marker as well as microglia activation in adulthood (P90).
Conclusion:
RAGE shedding via MMP9 represents a key regulatory mechanism by which oxidative stress interacts with neuroinflammatory conditions. The circular pathway described earlier constitutes a positive feed forward process by which inflammation and oxidative stress amplify each other in a process particularly damaging to PVI/PNN, at least in ACC. This vicious circle might explain the persistence of the observed cellular damage between peripuberty and adulthood and its disruption by MMP9 inhibitor after the second hit hold promise for preventive treatment approaches.
Background:
A hallmark of the pathophysiology of schizophrenia is a dysfunction of parvalbumin-expressing fast-spiking interneurons (PVI), which are essential for neuronal synchrony during sensory ...and cognitive processing. Oxidative stress and inflammation, as observed in schizophrenia, affects the highly metabolically active PVI. Some schizophrenia patients have decreased brain glutathione (GSH) levels due to genetic and functional origin. GSH dysregulation, by increasing vulnerability to oxidative stress and inflammation during early development, leads to impaired cortical circuitry, specifically the PVI and the perineuronal nets (PNN) that surround them.
Methods:
We tested whether a combined treatment of
N
-acetyl-cysteine (NAC) and enriched environment (EE), during adolescent, prevents the deleterious effect of oxidative insult on PVI and PNN. We used a transgenic mouse model with GSH deficit (GCLM KO) that shows SZ-related phenotype, increased oxidative stress, and microglia activation.
Results:
Here, we confirmed previous findings that an additional oxidative stress, using a dopamine reuptake inhibitor (GBR), in early postnatal days (P10-20) led to long-lasting effects in adult GCLM KO: increase in oxidative stress, activation of microglia, increase in MMP9-IR, and PVI and PNN impairment. These effects were completely reversed by the combination of NAC treatment (given between P21-35) and EE (during P35-56). Interestingly, MMP9-IR was also reversed by NAC treatment. The fast rhythmic oscillations reflecting neuronal synchronization of PVI was decreased in the GBR-treated GCLM KO and recovered by NAC/EE.
Conclusion:
Thus, an early oxidative insult induces long-lasting effects on PVI and PNN, which can be reversed by a combined NAC and EE, even after the challenge. In analogy, individuals carrying genetic risks to redox dysregulation potentially vulnerable to early-life insults could benefit from a combined pharmacological and psychosocial therapy.
Saccade-related burst neurons in the paramedian pontine reticular formation (PPRF) of the head-restrained monkey provide a phasic velocity signal to extraocular motoneurons for the generation of ...rapid eye movements. In the superior colliculus (SC), which directly projects to the PPRF, the motor command for conjugate saccades with the head restrained in a roll position is represented in a reference frame in between oculocentric and space-fixed coordinates with a clear bias toward gravity. Here we studied the preferred direction of premotor burst neurons in the PPRF during static head roll to characterize their frame of reference with respect to head and eye position. In 59 neurons (short-lead, burst-tonic, and long-lead burst neurons), we found that the preferred direction of eye displacement of these neurons changed, relative to head-fixed landmarks, in the horizontal-vertical plane during static head roll. For the short-lead burst neurons and the burst-tonic group, the change was about one-fourth of the amount of ocular counterroll (OCR) and significantly different from a head-centered representation. In the long-lead burst neurons, the rotation of the preferred direction showed a larger trend of about one-half of OCR. During microelectrical stimulation of the PPRF (9 sites in 2 monkeys), the elicited eye movements rotated with about one-half the amount of OCR. In a simple pulley model of the oculomotor plant, the noncraniocentric reference frame of the PPRF output neurons could be reproduced for recently measured pulley positions, if the pulleys were assumed to rotate as a function of OCR with a gain of 0.5. We conclude that the saccadic displacement signal is transformed from a representation in the SC with a clear bias to gravity to a representation in the PPRF that is closely craniocentric, but rotates with OCR, consistent with current concepts of the oculomotor plant.
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