Abstract
Altered oligodendrocyte structure and function is implicated in major psychiatric illnesses, including low cell number and reduced oligodendrocyte-specific gene expression in major depressive disorder (MDD). These features are also observed in the unpredictable chronic mild stress (UCMS) rodent model of the illness, suggesting that they are consequential to environmental precipitants; however, whether oligodendrocyte changes contribute causally to low emotionality is unknown. Focusing on 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp1), a crucial component of axoglial communication dysregulated in the amygdala of MDD subjects and UCMS-exposed mice, we show that altered oligodendrocyte integrity can have an unexpected functional role in affect regulation. Mice lacking Cnp1 (knockout, KO) displayed decreased anxiety- and depressive-like symptoms (i.e., low emotionality) compared with wild-type animals, a phenotypic difference that increased with age (3–9 months). This phenotype was accompanied by increased motor activity, but was evident before neurodegenerative-associated motor coordination deficits (⩽9–12 months). Notably, Cnp1KO mice were less vulnerable to developing a depressive-like syndrome after either UCMS or chronic corticosterone exposure. Cnp1KO mice also displayed reduced fear expression during extinction, despite normal amygdala c-Fos induction after acute stress, together implicating dysfunction of an amygdala-related neural network, and consistent with proposed mechanisms for stress resiliency. However, the Cnp1KO behavioral phenotype was also accompanied by massive upregulation of oligodendrocyte- and immune-related genes in the basolateral amygdala, suggesting an attempt at functional compensation. Together, we demonstrate that the lack of oligodendrocyte-specific Cnp1 leads to resilient emotionality. However, combined with substantial molecular changes and late-onset neurodegeneration, these results suggest the low Cnp1 seen in MDD may cause unsustainable and maladaptive molecular compensations contributing to the disease pathophysiology.
Highlights
Disruptions in neuronal signaling long have been the focus of research on major depressive disorder (MDD)
It is unlikely that changes were due to repeated testing as a pattern of decreased emotionality in WT mice would be expected, Cnp1KO-specific memory-related events cannot be ruled out (See Fear conditioning tests)
Focusing on an oligodendrocyte gene (Cnp1) that is critical for neuronal support and that is dysregulated in MDD, we tested
Summary
Disruptions in neuronal signaling long have been the focus of research on major depressive disorder (MDD). In the amygdala and prefrontal cortex of MDD subjects, previously reported decreases in glial cell number were attributed to reduced oligodendrocyte number,[11,12] consistent with patterns of downregulation of oligodendrocyte-related transcripts in amygdala[13] and nearby temporal cortex.[14] Changes in NG2 cells, a cell type sharing a common lineage with oligodendrocytes,[15,16] have been associated with depression-related characteristics in rodents Both chronic corticosterone exposure and chronic stress in rodents decreased cortical and limbic oligodendrocyte[17] and NG2 cell proliferation.[18,19] Rats given electroconvulsive seizure therapy, an antidepressant treatment for otherwise non-responsive MDD subjects, showed increased proliferation of NG2 cells in the amygdala and hippocampus.[18,20,21] evidence suggests that oligodendrocytes, a crucial element for maintaining optimal neuronal function, may be vulnerable to stress-related insults and may contribute to the pathophysiology of MDD
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