Behavioral Phenotype Of Cathepsin D-deficient Mice

Bipolar disorder (BD) is a severe neuropsychiatric disease characterized by recurring episodes of mania and depression. Manic patients often appear elevated mood, feels abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced as a result of disturbed biological rhythm. Characterized by low mood, patients in depressive episode may be lack of interest, psychomotor suppression, along with useless and helpless and the sense of sin, and even suicide. Psychology, hormones and drugs can trigger a manic or depressive episode, or cause manic-depressive state of transformation. Although there has made gains in clinical and basic research on BD, the exact etiology and pathogenesis is unknown so far. To explore the mechanism underlie BD so as to seek a safe and effective way for treatment is of vital urgence. However, because of the ethical concerns and technical limitations, research using patients’ specimens is increasingly difficut. Ideal animal model should have good face validity, structure validity and predictive validity, and should simulate human BD symptoms in many aspect including behavior and inherent phenotype. Studies on the neurobiological mechanisms of BD have been greatly hindered by the lack of adequate animal models. Therefore, to establish ideal animal model for BD is of great significance.Cathepsin D (CTSD), an aspartic protease in the endosomal-lysosomal system, participate to a great deal of physical function such as degradation of functional protein, antigen presenting, and degradation of cytoskeleton so as to regulate autophagy and apoptosis. Human neuronal ceroid lipofuscinoses (NCLs) are a family of neurodegenerative, lysosomal storage disorders characterized by the progressive neuronal accumulation of the auto-fluorescent storage material lipofuscin and severe neurodegeneration. Despite the genetic heterogeneity, the NCLs share certain clinical features including progressive epileptic seizures, visual failure, and progressive neuropsychological deficits, including sleep-disturbance, agitation, hyperactivity, depression, and aggressive behavior. Of the pathogenic mutations leading to NCLs, deficiency of CTSD result in the CLN10 form, the only disorder classified as an NCL onset in the immediately newborn period. The CTSD-knockout mouse appears phenotypically normal at birth through the first two weeks of life but starts to lose weight, develop seizures, and become blind during the third week. Animals die prematurely at around postnatal day 26, presenting neuropathological changes closely resembling those in patients with CLN10 disease in terms of autofluorescent ceroid/lipofuscin accumulation and neuron loss, particularly within the thalamus, hippocampus, and cerebral cortex. Interestingly, CTSD-deficient mice exhibit hyperactivity, a typical symptom in human mania. However, the behavioral phenotype of CTSD-deficient mice has not been analyzed in detail, especially in adult animals, since these mice die prematurely.Using CTSD heterozygous (CTSD HET) knockout mice, which do not have apparent developmental impairments or severe neuropathological symptoms, we were able to perform a series of behavioral analyses and establish a potential link between CTSD and psychiatric disorders. Detailed behavioral analysis revealed that CTSD HET mice display an overall behavioral profile that is similar to human mania, including hyperlocomotion, sensitivity to psychostimulant drugs, sleep-disturbance, and reduced anxiety-like behavior. However, under stressful conditions CTSD HET mice manifest depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. In addition, CTSD HET mice display stress-induced hypersecretion of corticosterone. Chronic administration of lithium chloride or valproic acid, two clinically effective mood stabilizers, reduces the extremes in behavior.Further more, CTSD-deficient mice showed early onset of mixed mania/depression-like state which is consistant with the selective early onset of GABAergic neurodegeneration. Injection of GABA or optogentic exciting GABAergic neuron in VPM/VPL rescue the altered behavior of CTSD-HET/VGAT(+) mice.These findings suggest an important role for CTSD in the regulation of mood stabilization, and establish the CTSD-deficient mouse as a putative animal model of BD.