Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm(−/−) knockout mice

Abstract

Enhanced oxidative stress or deficient oxidative stress response in the brain is associated with neurodegenerative disorders and behavioral abnormalities. Previously we generated a knockout mouse line lacking the gene encoding γ-glutamylcysteine ligase modifier subunit (GCLM). Gclm(−/−) knockout (KO) mice are viable and fertile, yet exhibit only 9–35% of wild-type levels of reduced glutathione (GSH) in tissues, making them a useful model for chronic GSH depletion. Having the global absence of this gene, KO mice—from the time of conception and throughout postnatal life—experience chronic oxidative stress in all tissues, including brain. Between postnatal day (P) 60 and P100, we carried out behavioral phenotyping tests in adults, comparing male and female Gclm(−/−) with Gclm(+/+) wild-type (WT) littermates. Compared with WT, KO mice exhibited: subnormal anxiety in the elevated zero maze; normal overall exploratory open-field activity, but slightly more activity in the peripheral zones; normal acoustic startle and prepulse inhibition reactions; normal novel object recognition with increased time attending to the stimulus objects; slightly reduced latencies to reach a random marked platform in the Morris water maze; normal spatial learning and memory in multiple phases of the Morris water maze; and significantly greater hyperactivity in response to methamphetamine in the open field. These findings are in general agreement with two prior studies on these mice and suggest that the brain is remarkably resilient to lowered GSH levels, implying significant reserve capacity to regulate reactivity oxygen species—but with regional differences such that anxiety and stimulated locomotor control brain regions might be more vulnerable.

Molecular substrates of schizophrenia: homeostatic signaling to connectivity

“… 323 , 324 , 328 , 333 , 359 , 366 , 373 Furthermore, models in which stress-associated cascades are primarily perturbed have also displayed abnormalities in neurotransmission and behavior: for example, mice with glutathione deficiency show impairments in parvalbumin-positive interneurons, myelination, and behavior. 340 , 341 , 343 , 344 , 374 , 375 Several animal models have been designed to test the effect of stress cascades on neurodevelopment, including both prenatal and juvenile models of stress and immune activation. 322 , 376 , 377 These developmental stressors have been shown to affect neurotransmission, myelination, and even metabolism.…”

Oxidative stress and schizophrenia

“…Of interest, this mouse model displayed reduced PV immunoreactivity in the CA3 and dentate gyrus, as well as predicted deficits in gamma oscillations [49]. The animals also showed deficits in prepulse inhibition and hyperlocomotion selective to environmental novelty and stress, and in response to acute amphetamine injection [50, 51]. Oxidative stress is prominent in adolescence, but the behavioral phenotypes relevant to SZ become more prominent after puberty, suggesting an idea that oxidative stress may be involved in early stage of the pathological trajectory [49, 52].…”

Oxidative Imbalance and Anxiety Disorders

“…Chen and colleagues [148] used knockout mouse line lacking the gene encoding glutamate-cysteine ligase modifier subunit (GCLM), the first and the rate-limiting enzyme in the synthesis of GSH. These animals present reduced GSH levels in tissues.…”