Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders

Abstract

Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/-) have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG). The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophreniaenriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/ maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and serve as a promising candidate endophenotype of schizophrenia and other human psychiatric disorders.

Reversal of hippocampal neuronal maturation by serotonergic antidepressants

“…Similar changes in GC functions and/or in the state of GC maturation have been demonstrated in mice disrupted for the gene encoding alpha-CaMKII (27), brain-derived neurotrophic factor (44), or the glutamate receptor subunit GluK2/GluR6 (10,45). The deficiency in either of these genes has been shown to cause substantial behavioral abnormalities (27,46,47), which supports the idea that the GC dematuration can potentially cause dysfunction of the adult hippocampus. On the other hand, the increased GC excitability caused by the dematuration may improve some pathological conditions, such as reduced GC activity in animals exposed to chronic stress (7).…”

“…fluoxetine on expression of potential GC-specific maturation markers, desmoplakin, tryptophan-2,3-dioxygenase, and interleukin-1 receptor type I, whose expression is restricted to dentate GCs (27) and increases with postnatal development similarly to calbindin (Fig. S1).…”

“…In other words, fluoxetine reversed the late step of GC maturation. We have recently shown that dentate GCs stay "immature" in adults in mice heterozygous for alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) (27). The phenotype of these GCs is similar to that of dematurated GCs in fluoxetine-treated mice: Both alphaCaMKII-deficient and fluoxetine-treated GCs exhibit downregulation of mature molecular markers, suppression of c-Fos expression, increases in GC excitability, and greatly reduced frequency facilitation at the MF synapse.…”

“…We then examined properties of dentate-to-CA3 signal transmission mediated by MF, the axon of GC. The mature MF-CA3 pyramidal cell synapse is characterized by exceptionally strong frequency facilitation (13,27) (see Fig. 3A), a presynaptic enhancement of synaptic strength during higher-frequency transmission (31).…”

Chronic Fluoxetine Selectively Upregulates Dopamine D1-Like Receptors in the Hippocampus

“…This highly localized hippocampus-specific increase in D 1 -like ligand binding is in agreement with the lack of an increase in D 1 mRNA levels or D 1 -like ligand binding in the brain regions other than the hippocampus in most previous studies. We have previously demonstrated a similar marked increase in D 1 -like ligand binding that is restricted to the dentate gyrus and mossy fiber tract in mice heterozygous for a-calcium/calmodulin-dependent protein kinase II (Yamasaki et al, 2008). We have also shown that the dopaminergic modulation at the mossy fiber synapse is clearly enhanced in a subpopulation of mice lacking the schizophrenia susceptible gene dysbindin-1 (Kobayashi et al, 2011b).…”