So Yoen Choi

PI3Kγ is required for NMDA receptor–dependent long-term depression and behavioral flexibility

Phosphatidylinositol 3-kinase (PI3K) has been implicated in synaptic plasticity and other neural functions in the brain. However, the role of individual PI3K isoforms in the brain is unclear. We investigated the role of PI3Kγ in hippocampal-dependent synaptic plasticity and cognitive functions. We found that PI3Kγ has a crucial and specific role in NMDA receptor (NMDAR)-mediated synaptic plasticity at mouse Schaffer collateral–commissural synapses. Both genetic deletion and pharmacological inhibition of PI3Kγ disrupted NMDAR long-term depression (LTD) while leaving other forms of synaptic plasticity intact. Accompanying this physiological deficit, the impairment of NMDAR LTD by PI3Kγ blockade was specifically correlated with deficits in behavioral flexibility. These findings suggest that a specific PI3K isoform, PI3Kγ, is critical for NMDAR LTD and some forms of cognitive function. Thus, individual isoforms of PI3Ks may have distinct roles in different types of synaptic plasticity and may therefore influence various kinds of behavior.

Physiological and Pathological Significance of Dynamin-Related Protein 1 (Drp1)-Dependent Mitochondrial Fission in the Nervous System

Mitochondria are essential for proper neuronal morphogenesis and functions, as they are the major source of energy for neural development. The dynamic morphology of mitochondria determines the key functions of mitochondria. Several regulatory proteins such as dynamin-related protein 1 (Drp1) are required to maintain mitochondrial morphology via a balance between continuous fusion and fission. Activity of Drp1, a key regulator in mitochondrial fission, is modulated by multiple post-translation modifications and receptor interactions. In addition, numerous researches have revealed that the regulation of Drp1 activity and mitochondrial dynamics is closely associated with several neurodegenerative diseases such as Alzheimers and Parkinsons diseases. In this article, we concisely review the recent findings about the biological importance of Drp1-mediated mitochondrial fission in neurons under physiological and pathological conditions.

(ADP-ribose) polymerase 1 and AMP-activated protein kinase mediate progressive dopaminergic neuronal degeneration in a mouse model of Parkinson's disease

Genetic and epidemiologic evidence suggests that cellular energy homeostasis is critically associated with Parkinson’s disease (PD) pathogenesis. Here we demonstrated that genetic deletion of Poly (ADP-ribose) polymerase 1 completely blocked 6-hydroxydopamine-induced dopaminergic neurodegeneration and related PD-like symptoms. Hyperactivation of PARP-1 depleted ATP pools in dopaminergic (DA) neurons, thereby activating AMP-activated protein kinase (AMPK). Further, blockade of AMPK activation by viral infection with dominant-negative AMPK strongly inhibited DA neuronal atrophy with moderate suppression of nuclear translocation of apoptosis-inhibiting factor (AIF), whereas overactivation of AMPK conversely strengthened the 6-OHDA-induced DA neuronal degeneration. Collectively, these results suggest that manipulation of PARP-1 and AMPK signaling is an effective therapeutic approach to prevent PD-related DA neurodegeneration.

The expression of non-clustered protocadherins in adult rat hippocampal formation and the connecting brain regions

Non-clustered protocadherins (PCDHs) are calcium-dependent adhesion molecules which have attracted attention for their possible roles in the neuronal circuit formation during development and their implications in the neurological disorders such as autism and mental retardation. Previously, we found that a subset of the non-clustered PCDHs exhibited circuit-dependent expression patterns in thalamo-cortical connections in early postnatal rat brain, but such patterns disappeared in adulthood. In this study, we identified that the non-clustered PCDHs showed differential expression patterns along the septotemporal axis in the subregions of adult hippocampus and dentate gyrus with topographical preferences. The expressions of PCDH1, PCDH9, PCDH10 and PCDH20 showed septal preferences, whereas the expressions of PCDH8, PCDH11, PCDH17 and PCDH19 showed temporal preferences, suggesting that they play roles in the formation/maintenance of intrahippocampal circuits. PCDHs also exhibited the region-specific expression patterns in the areas connected to hippocampal formation such as entorhinal cortex, lateral septum, and basolateral amygdaloid complex. Furthermore, the expression levels of three PCDHs (PCDH8, PCDH19 and PCDH20) were regulated by the electroconvulsive shock stimulation of the brain in the adult hippocampus and dentate gyrus. These results suggest that non-clustered PCDHs are involved in the maintenance and plasticity of adult hippocampal circuitry.

Phosphorylation of c-Jun in Avian and Mammalian Motoneurons In Vivo during Programmed Cell Death: An Early Reversible Event in the Apoptotic Cascade

c-Jun is a transcription factor that is involved in various cellular events, including apoptotic cell death. For example, phosphorylation of c-Jun is one of the earliest biochemical changes detected in dying sympathetic neurons after NGF deprivation in vitro. However, currently, it is not known whether a similar molecular event is involved in the developmental programmed cell death (PCD) of neurons in vivo.We observed that only a subpopulation of motoneurons (MNs) exhibit c-Jun phosphorylation during the PCD period in chick [embryonic day 5 (E5)-E12] and mouse (E13-E18) embryos. Experimental perturbation of MN survival-promoting signals by limb bud removal (reduced signals) or by activity blockade (increased signals) in the chick embryo demonstrated that the presence of those signals is negatively correlated with the number of c-Jun-phosphorylated MNs. This suggests that insufficient survival signals (e.g., neurotrophic factors) may induce c-Jun phosphorylation of MNs in vivo. Consistent with the idea that c-Jun phosphorylation is a reversible event during normal PCD of MNs, we found that c-Jun phosphorylation was transiently observed in a subpopulation of mouse MNs rescued from PCD by deletion of the proapoptotic gene Bax. Inhibition of c-Jun signaling significantly reduced MN death in chick embryo, indicating that activation of c-Jun signaling is necessary for the PCD of MNs. Together, c-Jun phosphorylation appears to be required for the initiation of an early and reversible event in the intracellular PCD cascade in vivo after loss of survival-promoting signals such as neurotrophic factors.

Preso, A Novel PSD-95-Interacting FERM and PDZ Domain Protein That Regulates Dendritic Spine Morphogenesis

PSD-95 is an abundant postsynaptic density (PSD) protein involved in the formation and regulation of excitatory synapses and dendritic spines, but the underlying mechanisms are not comprehensively understood. Here we report a novel PSD-95-interacting protein Preso that regulates spine morphogenesis. Preso is mainly expressed in the brain and contains WW (domain with two conserved Trp residues), PDZ (PSD-95/Dlg/ZO-1), FERM (4.1, ezrin, radixin, and moesin), and C-terminal PDZ-binding domains. These domains associate with actin filaments, the Rac1/Cdc42 guanine nucleotide exchange factor βPix, phosphatidylinositol-4,5-bisphosphate, and the postsynaptic scaffolding protein PSD-95, respectively. Preso overexpression increases the density of dendritic spines in a manner requiring WW, PDZ, FERM, and PDZ-binding domains. Conversely, knockdown or dominant-negative inhibition of Preso decreases spine density, excitatory synaptic transmission, and the spine level of filamentous actin. These results suggest that Preso positively regulates spine density through its interaction with the synaptic plasma membrane, actin filaments, PSD-95, and the βPix-based Rac1 signaling pathway.

Induction of ezrin-radixin-moesin molecules after cryogenic traumatic brain injury of the mouse cortex

Traumatic brain injury promotes rapid induction of microglial cells and infiltration of peripheral macrophages to the injury sites. Such inflammatory responses are mediated by the activation and migration of immune cells, which are influenced by the actin cytoskeleton remodeling. In this study, we observed that the phosphorylation and expressions of ezrin–radixin–moesin (ERM) proteins, which are linkers for cell surface with actin cytoskeleton, are induced in the activated microglia/macrophages, whereas ERM molecules are only marginally expressed in quiescent microglia in the normal brain. These results suggest that ERM activation in the injury penumbra is implicated in the inflammatory immune responses after traumatic brain injury.

Expression of connexin29 and 32 in the penumbra region after traumatic brain injury of mice.

Connexins (Cx) are transmembrane proteins forming vertebrate gap junction channels for direct cell–cell communication. We found that the expressions of two Cx family members, Cx29 and Cx32, were progressively increased in the sharp border of injury penumbra regions after cryotraumatic brain injury. Although these two Cxs are expressed exclusively in the oligodendrocytes in the normal cerebral cortex, their expressions were increased in the astrocytes and microglia localized in the injury border. Highly selective induction of Cxs in the injury border suggests that altered Cxs may contribute to the propagations of injury-related and/or regeneration signals after acute brain injury.

Drp1-mediated mitochondrial dynamics and survival of developing chick motoneurons during the period of normal programmed cell death

Mitochondrial morphology is dynamically remodeled by fusion and fission in neurons, and this process is implicated in nervous system development and pathology. However, the mechanism by which mitochondrial dynamics influence neuronal development is less clear. In this study, we found that the length of mitochondria is progressively reduced during normal development of chick embryo motoneurons (MNs), a process partly controlled by a fission‐promoting protein, dynamin‐related protein 1 (Drp1). Suppression of Drp1 activity by gene electroporation of dominant‐negative mutant Drp1 in a subset of developing MNs increased mitochondrial length in vivo, and a greater proportion of Drp1‐suppressed MNs underwent programmed cell death (PCD). By contrast, the survival of nontransfected MNs in proximity to the transfected MNs was significantly increased, suggesting that the suppression of Drp1 confers disadvantage during the competition for limited survival signals. Because we also monitored perturbation of neurite outgrowth and mitochondrial membrane depolarization following Drp1 suppression, we suggest that impairments of ATP production and axonal growth may be downstream factors that influence the competition of MNs for survival. Collectively, these results indicate that mitochondrial dynamics are required for normal axonal development and competition‐dependent MN PCD.—Choi, S. Y., Kim, J. Y., Kim, H.‐W., Cho, B., Cho, H. M., Oppenheim, R. W., Kim, H., Rhyu, I. J., Sun, W. Drp1‐mediated mitochondrial dynamics and survival of developing chick motoneurons during the period of normal programmed cell death. FASEB J. 27, 51–62 (2013). www.fasebj.org

Different expression patterns of Phactr family members in normal and injured mouse brain

Phosphatase and actin regulators (Phactrs) are a novel family of proteins expressed in the brain, and they exhibit both strong modulatory activity of protein phosphatase 1 and actin-binding activity. Phactrs are comprised of four family members (Phactr1-4), but their detailed expression patterns during embryonic and postnatal development are not well understood. We found that these family members exhibit different spatiotemporal mRNA expression patterns. Phactr4 mRNA was found in neural stem cells in the developing and adult brains, whereas Phactr1 and 3 appeared to be expressed in post-mitotic neurons. Following traumatic brain injury which promotes neurogenesis in the neurogenic region and gliogenesis in the injury penumbra, the mRNA expression of phactr2 and 4 was progressively increased in the injury penumbra, and phactr4 mRNA and protein induction was observed in reactive astrocytes. These differential expression patterns of phactrs imply specific functions for each protein during development, and the importance of Phactr4 in the reactive gliosis following brain injury.