Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation

Abstract

The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis.

DNA methylation patterns of protein coding genes and long noncoding RNAs in female schizophrenic patients

“…4), suggesting the disease mechanism of SCZ with different subtypes may have the same pathways. Our results were consistent with the previous findings that most susceptibility genes associated with SCZ were functional in neuron [O'Dushlaine et al, 2011;Kahler et al, 2008;Favre et al, 2012]. In addition, our results further implicated that these 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 neuron related genes might also affect SCZ development through DNA methylation aberration except for the genetic way.…”

An analysis of entorhinal cortex projections to the dentate gyrus, hippocampus, and subiculum of the neonatal macaque monkey

“…Taken together, these data indicate that the topographical organization of the primate hippocampal formation circuitry is established by birth, but that there is continued refinement of many aspects of hippocampal connectivity, at least for many months after birth (Favre et al, ; Jabes et al, , ; Lavenex et al, ). Accumulating evidence suggests that the differential maturation of distinct hippocampal circuits contributes to the emergence of different “hippocampus‐dependent” memory processes over the course of postnatal development (Lavenex and Lavenex Banta, ).…”

“…Accumulating evidence suggests that the differential maturation of distinct hippocampal circuits contributes to the emergence of different “hippocampus‐dependent” memory processes over the course of postnatal development (Lavenex and Lavenex Banta, ). Thus, factors that affect hippocampal development at any point during this period could have serious consequences for normal cognitive development (Ribordy et al, ) and for the emergence of neurodevelopmental conditions such as schizophrenia (Favre et al, ).…”

“…And, are the various topographic gradients of fiber distribution also established by this age? The answers to these questions provide new information that, along with recent quantitative neuroanatomical (Jabes et al, , ), genetic (Favre et al, ; Lavenex et al, ) and behavioral (Lavenex and Lavenex, ) studies, provide a clearer understanding of the neurobiological underpinnings for the development of the capacity for episodic or spatial‐relational memory in the nonhuman primate.…”

Commentary

“…Indeed, it is now well established that the hippocampal formation is not a single structure, but comprises a number of distinct regions and circuits Lavenex & Amaral, 2000) that subserve different computational processes and memory functions (Copara et al, 2014;Kesner, Lee, & Gilbert, 2004;Nakashiba et al, 2012). Our recent work at the genetic and neuroanatomical levels revealed that different hippocampal regions mature at different times during development (Favre, Banta Lavenex, & Lavenex, 2012a, 2012bJabès, Banta Lavenex, Amaral, & Lavenex, 2010Lavenex, Banta Lavenex, & Amaral, 2007;Lavenex, Sugden, Davis, Gregg, & Banta Lavenex, 2011). These findings, together with our studies of the development of human spatial memory (Ribordy, Jabès, Banta Lavenex, & Lavenex, 2013;Ribordy Lambert, Lavenex & Banta Lavenex, 2015), support the hypothesis that the differential maturation of distinct hippocampal circuits might underlie the differential emergence of specific ''hippocampus-dependent'' memory processes, culminating in the emergence of adult-like episodic memory concomitant with the maturation of all hippocampal circuits .…”