Original researchImpaired Autophagy in Hilar Mossy Cells of the Dentate Gyrus and Its Implication in Schizophrenia
Introduction
Schizophrenia (SCZ) is a chronic debilitating disorder characterized by positive and negative symptoms, disorganization and cognitive deficits. Etiologically, both genetic and environmental factors contribute to the development of SCZ. To date, its pathogenesis has not been well defined. Developmental or synaptic alternations have been documented in SCZ, and especially the impaired adult neurogenesis has been implicated in SCZ (Kempermann et al., 2008, Balu and Coyle, 2011, Ming and Song, 2011). DTNBP1 (dystrobrevin-binding protein 1), which encodes dysbindin-1, is a leading susceptibility gene of SCZ (Straub et al., 2002, Fanous and Kendler, 2008). The sandy (sdy) mutant, which carries a spontaneously occurring large deletion in the Dtnbp1 gene on the DBA/2J inbred strain (Li et al., 2003), is an appropriate mouse model of SCZ (Feng et al., 2008, Hattori et al., 2008, Takao et al., 2008, Bhardwaj et al., 2009).
Three isoforms of dysbindin-1 (dysbindin-1A, 1B and 1C) in primates have been identified (Talbot et al., 2009). Human dysbindin-1A, the longest isoform with 351 amino acids (aa), differs from 1B in the C-terminus, and differs from 1C in the N-terminus. However, there is no known mouse or rat ortholog of human dysbindin-1B (Talbot et al., 2009). In the temporal lobe, about 92% of the schizophrenia cases displayed synaptic dysbindin-1A reductions without alterations in other dysbindin-1 isoforms in the auditory association cortices. In contrast, in the hippocampal formation (HF), most SCZ cases displayed normal levels of synaptic dysbindin-1A, but showed reductions in 1B and 1C (Talbot et al., 2011). Our recent findings revealed that dysbindin-1C, not 1A, is required for the survival of hilar mossy cells and the maturation of adult newborn neurons in the dentate gyrus (DG), suggesting that reduced dysbindin-1C in the schizophrenic HF is important for the development of cognitive deficits (Wang et al., 2014). However, the underlying mechanism of hilar mossy cell loss is unknown.
Dysbindin-1A is a subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) (Li et al., 2003, Wang et al., 2014). BLOC-1 complex functions in lysosomal trafficking and biogenesis of lysosome-related organelles (Wei and Li, 2013). Mouse dysbindin-1C mRNA lacks exons 1–4 of 1A and contains an alternative promoter in intron 4, thus resulting in a downstream start codon on exon 5 of 1A and a deletion of the N-terminal 81 residues (Li et al., 2003). Dysbindin-1C does not reside in the BLOC-1 complex and has a distinct spatial and temporal expression pattern in the central nervous system compared with 1A due to the utilization of a different promoter (Wang et al., 2014). In addition, dysbindin-1C regulates adult hippocampal neurogenesis in both non-cell autonomous and BLOC-1 independent manners (Wang et al., 2014). This suggests that dysbindin-1C regulates the survival of hilar mossy cells independent of BLOC-1 complex. A default nucleus localization signal may lie on the N-termini of dysbindin-1A and 1B as lack of this sequence in 1C leads to its cytosolic retention (Fei et al., 2010). The different subcellular distribution may underlie their difference in function, which requires further investigation. Both dysbindin-1A and 1C contain the 97–118 aa region that is required for its interaction with necdin (Ma et al., 2011). Necdin is a p53-interacting protein expressed predominantly in post-mitotic neurons and is required for neuronal survival (Hasegawa and Yoshikawa, 2008). Whether dysbindin-1C is involved in this pathway for the regulation of hilar mossy cell survival is unknown.
In this study, by using sdy mice, in which both dysbindin-1A and 1C are deleted (1A−/1C−) (Li et al., 2003), we explore the molecular mechanism of dysbindin-1C in regulating the hilar mossy cell survival by comparing with the wild-type controls (1A+/1C+), and the muted (mu) (Zhang et al., 2002) or pallid (pa) mice (Huang et al., 1999), in which only dysbindin-1A is destabilized while 1C is unaltered (1A−/1C+) (Wang et al., 2014). We found that dysbindin-1C, but not 1A, is involved in autophagy which may be required for the survival of hilar mossy cells.
Section snippets
No positive TUNEL signals in the DG of sdy mice
We recently reported that the number of hilar mossy cells in the DG of sdy mice was significantly decreased compared with wild-type controls. In contrast, there was no significant difference in the number of hilar GABA interneurons in the DG between sdy mice and controls (Wang et al., 2014). This result indicates that loss of dysbindin-1C selectively compromises the survival of hilar mossy cells in the DG. To explore the underlying mechanism of mossy cell loss, we tested whether the mossy cells
Discussion
In this study, we found that dysbindin-1C, which is localized in glutamatergic mossy cells of the hilus in the DG (Wang et al., 2014), is required for the maintenance of their survival by functioning in regulating autophagy. This highlights the relationship between impaired autophagy and the pathogenesis of SCZ. Our results support the importance of decreased dysbindin-1C found in the schizophrenic HF (Talbot et al., 2011) for the development of mossy cell degeneration. In this sense,
Mice
The sdy mutant (sdy/sdy, loss of dysbindin-1) and its wild-type control DBA/2J (DBA) mice, the mu mutant (mu/mu, loss of muted protein) and its wild-type control CHMU/Le, and the pa mutant (pa/pa, loss of pallidin) and its wild-type control C57BL/6J (B6) were originally obtained from the Jackson Laboratory, transferred from Dr. Richard T. Swank's laboratory and bred in the animal facility of the Institute of Genetics and Developmental Biology (IGDB), Chinese Academy of Sciences. All procedures
Acknowledgements
This work was partially supported by grants from the National Natural Science Foundation of China (Nos. 91332116 and 31230046), from the National Basic Research Program of China (No. 2014CB942803) and from Chinese Academy of Sciences (No. KJZD-EW-L08).
References (33)
- et al.
Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia
Neurosci. Biobehav. Rev.
(2011) - et al.
Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila
Cell
(2007) - et al.
Behavioral characterization of dysbindin-1 deficient sandy mice
Behav. Brain Res.
(2009) - et al.
Caspase-mediated cleavage of ATG6/Beclin-1 links apoptosis to autophagy in HeLa cells
Cancer Lett.
(2009) - et al.
Nucleocytoplasmic shuttling of dysbindin-1, a schizophrenia-related protein, regulates synapsin I expression
J. Biol. Chem.
(2010) - et al.
Dysbindin deficiency in sandy mice causes reduction of snapin and displays behaviors related to schizophrenia
Schizophr. Res.
(2008) - et al.
Behavioral abnormalities and dopamine reductions in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia
Biochem. Biophys. Res. Commun.
(2008) - et al.
Mutations in the BLOC-1 subunits dysbindin and muted generate divergent and dosage-dependent phenotypes
J. Biol. Chem.
(2014) - et al.
The BLOC interactomes form a network in endosomal transport
J. Genet. Genomics
(2007) - et al.
Adult neurogenesis in the mammalian brain: significant answers and significant questions
Neuron
(2011)
Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death
Curr. Biol.
Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia
Am. J. Hum. Genet.
Physical and functional interactions of neuronal growth suppressor necdin with p53
J. Biol. Chem.
Dysbindin-1C is required for the survival of hilar mossy cells and the maturation of adult newborn neurons in dentate gyrus
J. Biol. Chem.
Inhibition of macroautophagy triggers apoptosis
Mol. Cell Biol.
DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release
J. Cell Biol.
Cited by (26)
The protective effect of the endocannabinoid system in neurotoxin-induced damage to hippocampal neurons: a focus on light and electron microscopy
2023, Neurobiology and Physiology of the Endocannabinoid SystemMossy cells of the dentate gyrus: Drivers or inhibitors of epileptic seizures?
2022, Biochimica et Biophysica Acta - Molecular Cell ResearchCitation Excerpt :Finally, it has been suggested that MCs display low level of autophagy. The decreased level of waste removal capacity during high metabolic demands may also the reason for their vulnerability [50]. These findings led to the hypothesis that MC loss may result in TLE development.
Heme metabolism, mitochondria, and complex I in neuropsychiatric disorders
2020, Neuroprotection in Autism, Schizophrenia and Alzheimer's DiseaseHeme metabolism, mitochondria, and complex I in neuropsychiatric disorders
2019, Neuroprotection in Autism, Schizophrenia and Alzheimer's disease