Mitochondrial Regulation of Synaptic Plasticity in the Hippocampus

Abstract

Synaptic mechanisms of plasticity are calciumdependent processes that are affected by dysfunction of mitochondrial calcium buffering. Recently, we observed that mice deficient in mitochondrial voltage-dependent anion channels, the outer component of the mitochondrial permeability transition pore, have impairments in learning and hippocampal synaptic plasticity, suggesting that the mitochondrial permeability transition pore is involved in hippocampal synaptic plasticity. In this study, we examined the effect on synaptic transmission and plasticity of blocking the permeability transition pore with low doses of cyclosporin A and found a deficit in synaptic plasticity and an increase in base-line synaptic transmission. Calcium imaging of presynaptic terminals revealed a transient increase in the resting calcium concentration immediately upon incubation with cyclosporin A that correlated with the changes in synaptic transmission and plasticity. The effect of cyclosporin A on presynaptic calcium was abolished when mitochondria were depolarized prior to cyclosporin A exposure, and the effects of cyclosporin A and mitochondrial depolarization on presynaptic resting calcium were similar, suggesting a mitochondrial locus of action of cyclosporin A. To further characterize the calcium dynamics of the mitochondrial permeability transition pore, we used an in vitro assay of calcium handling by isolated brain mitochondria. Cyclosporin A-exposed mitochondria buffered calcium more rapidly and subsequently triggered a more rapid mitochondrial depolarization. Similarly, mitochondria lacking the voltagedependent anion channel 1 isoform depolarized more readily than littermate controls. The data suggest a role for the mitochondrial permeability transition pore and voltage-dependent anion channels in mitochondrial synaptic calcium buffering and in hippocampal synaptic plasticity.The mitochondrial permeability transition pore (MPT) 1 is a complex believed to be composed of the voltage-dependent anion channel (VDAC) in the mitochondrial outer membrane, the adenine nucleotide transporter in the inner membrane, and cyclophilin-D in the matrix and is found in mitochondria of all eukaryotic cells. Although the majority of research on the function of the MPT and its components has focused on apoptosis (1-3), the MPT has recently been shown to play a role in learning and synaptic plasticity in mice (4) as well as in other physiological cellular functions (5). In both pathological and physiological functions, the induction of the MPT is mediated by mitochondrial calcium influx above a certain threshold, and once opened, the MPT conducts small substrates and ions out of the mitochondrial matrix (6). It has therefore been proposed that following physiologic calcium influx into the mitochondrial matrix, formation of the MPT might be a physiological mechanism of mitochondrial calcium release (5).We are interested in determining the role of mitochondrial calcium regulation in synaptic function. The most extensively characterized synapses in the m...

Neuronal Per Arnt Sim (PAS) Domain Protein 4 (NPAS4) Regulates Neurite Outgrowth and Phosphorylation of Synapsin I

“…Both phosphorylated and nonphosphorylated Syn I regulate neuronal development (36 -38). The anti-p-Syn I antibodies used in this study recognize phosphorylated Ser 553 of SYN I, which is known to be phosphorylated by CDK5 (30,31). Although previous DNA microarrays and ChIP-Seq studies did not reveal that CDK5 or CDK5-coactivator p35 is a target of NPAS4 (13,46), CDK5 is essential for neurite outgrowth (39 -41) and has roles in the physiological regulation of cytoskeletal components during neurotransmitter release via phosphorylation of SYN I (30).…”

“…Cells-The anti-p-Syn I antibodies used in this study recognize phosphorylated Ser 553 of SYN I, which is known to be a substrate of CDK5 (30,31). Therefore, we measured CDK5 expression levels and its role for p-SYN I expression levels in NPAS4-overexpressed cells.…”

Mechanisms of Prolonged Presynaptic Ca2+Signaling and Glutamate Release Induced by TRPV1 Activation in Rat Sensory Neurons

“…A similar secondary [Ca 2ϩ ] i transient during the CGP37157 removal has been also reported in the cell body of DRG neurons (Baron and Thayer, 1997). Ca 2ϩ release from the matrix can also be mediated by the mitochondrial permeability transition pore (MPT or PTP) (Nicholls and Budd, 2000; Thayer et al, 2002;Newmeyer and Ferguson-Miller, 2003), and the voltage-dependent anion channel, which is the principal molecular component of the MPT, has been implicated in synaptic plasticity (Jonas et al, 1999;Levy et al, 2003;Jonas, 2004). We therefore examined the effect of the MPT inhibitor cyclosporin A (CsA) on the capsaicin-induced [Ca 2ϩ ] i elevation.…”

“…5D) (Zucker and Regehr, 2002;Hollenbeck, 2005;Wimmer et al, 2006). The function and mechanisms of Ca 2ϩ transport by presynaptic mitochondria vary substantially among synapses and are likely specialized according to the signaling needs at a particular synapse (Tang and Zucker, 1997;Billups and Forsythe, 2002;Jonas et al, 2003;Levy et al, 2003;Yang et al, 2003;Garcia-Chacon et al, 2006). Factors contributing to such specialization include the number and the architecture of presynaptic mitochondria, their proximity to the active zones and Ca 2ϩ channels, and the presence of other Ca 2ϩ clearance mechanisms that compete with mitochondria for Ca 2ϩ (Nguyen et al, 1997;Zenisek and Matthews, 2000;Guo et al, 2005).…”

Mitochondria and the central nervous system: searching for a pathophysiological basis of psychiatric disorders

“…[11][12][13] Several prominent signaling pathways that stimulate mitochondrial biogenesis and energy metabolism, while simultaneously regulating neuroplasticity, have been demonstrated. 13 Mitochondria are distributed throughout the length of axons and presynaptic terminals.…”