Journal of Neuroscience Research 92:819–824 (2014)
Mini-Review Intracellular Zn21 Signaling in Cognition Atsushi Takeda,1,2* Hiroaki Fujii,2 Tatsuya Minamino,1 and Haruna Tamano1 1
Department of Bioorganic Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan 2 Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
Brain zinc homeostasis is strictly controlled under healthy conditions, indicating the importance of zinc for physiological function in the brain. A part of zinc in the brain exists in the synaptic vesicles, is released from a subclass of glutamatergic neurons (i.e., zincergic neurons), and serves as a signal factor (Zn21 signal) in the intracellular (cytosol) compartment as well as in the extracellular compartment. Zn21 signaling is dynamically linked to glutamate signaling and may be involved in synaptic plasticity, such as long-term potentiaion and cognitive activity. In zincergic synapses, intracellular Zn21 signaling in the postsynaptic neurons, which is linked to Zn21 release from zincergic neuron terminals, plays a role in cognitive activity. When nonzincergic synapses participate in cognition, on the other hand, it is possible that intracellular Zn21 signaling, which is due mainly to Zn21 release from the internal stores and/or metallothioneins, also is involved in cognitive activity, because zinc-dependent system such as zinc-binding proteins is usually required for cognitive process. Intracellular Zn21 dynamics may be modified via an endocrine system activity, glucocorticoid secretion in both zincergic and nonzincergic neurons, which is linked to a long-lasting change in synaptic efficacy. On the basis of the evidence of cognitive decline caused by the lack and/or the blockade of synaptic Zn21 signaling, this article summarizes the involvement of intracellular Zn21 signaling in zincergic synapses in cognition and a hypothetical involvement of that in nonzincergic synapses. VC 2014 Wiley Periodicals, Inc. Key words: Zn21 signal; cognition; hippocampus; glucocorticoid; glutamate
Zinc homeostasis is essential for human health (Maret and Sandstead, 2008; Prasad, 2012, 2013). The regulation of zinc homeostasis in the living body is tightly controlled by both intestinal absorption and intestinal and renal excretions (King et al., 2000). Zrt-Irt-like proteins (ZIP), which are responsible for the movement of zinc into the cytoplasm, and the zinc transporter (ZnT) family, which is responsible for the transport of zinc out of the cytoplasm, are involved in the absorption and excretion of zinc to maintain zinc homeostasis in the living body C 2014 Wiley Periodicals, Inc. V
(Fukada and Kambe, 2011). Serum zinc is thought to be a major pool of zinc in the living body to transfer zinc to the tissues and organs. On the other hand, brain zinc homeostasis is also strictly controlled under healthy conditions, indicating the importance of zinc for functioning in the brain and for brain development (Burdette and Lippard, 2003; Georgieff, 2007; Takeda and Tamano, 2009). Approximately 80% of total brain zinc exists as zinc metalloproteins. The residual zinc amount is histochemically reactive as revealed by Timm’s sulfide-silver staining method (Frederickson 1989; Frederickson and Danscher, 1990), because the lack of ZnT3 protein, which is responsible for the movement of zinc from the cytoplasm into the synaptic vesicles, results in a 20% reduction of the total amount of brain zinc (Palmiter et al., 1996; Cole et al., 1999). Although the chemical form of zinc in the synaptic vesicles is unknown, vesicular zinc composes a major pool for intracellular Zn21 signaling (Takeda et al., 2013). On the other hand, Zn21 levels, except for vesicular Zn21, are estimated to be less than 5% of the total Zn21 amount in the hippocampus and cerebral cortex (Lee et al., 2011). Zn21 is released with glutamate from a subclass of glutamatergic neurons, i.e., zincergic neurons, in the brain and modulates zincergic synapse activity (Frederickson 1989; Frederickson and Danscher, 1990). The hippocampus and amygdala are enriched with zincergic synapses. Synaptic Zn21 signaling may be linked to cognitive and emotional behavior (Takeda, 2010, 2011). Therefore, the spatiotemporal role of synaptic Zn21 signaling in the hippocampus and amygdala is important for understanding cognitive and emotional behavior. Synaptic plasticity, such as long-term-potentiation (LTP), is believed to be a cellular mechanism in memory *Correspondence to: Atsushi Takeda, Department of Bioorganic Chemistry &Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422–8526, Japan. E-mail: [email protected] Received 18 December 2013; Revised 30 January 2014; Accepted 21 February 2014 Published online 10 April 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jnr.23385
820
Takeda et al.
Fig. 1. Static Zn21 imaging in the hippocampus. Intracellular and extracellular Zn21 levels are imaged with ZnAF-2DA (left) and ZnAF-2 (right). The fluorescence is strongly observed in the hilus (H) and the stratum lucidam (SL).
and has been widely studied at glutamatergic synapses in the brain, especially in the hippocampus. Glutamatergic neurons compose neural circuits in the hippocampus and amygdala to process the information in memory. On the other hand, it is well known that hypothalamic-pituitaryadrenal (HPA) axis activity, i.e., glucocorticoid secretion, can potentiate glutamatergic neuron activity (Sandi, 2011) and that HPA axis activity is critical not only for cognitive behavior but also for emotional behavior (Howland and Wang, 2008; Jo€els and Karst, 2012). Glucocorticoid signaling may modify synaptic Zn21 signaling and is linked to cognitive and emotional behavior (Takeda and Tamano, 2012). On the basis of the evidence of cognitive decline caused by the lack and/or the blockade in synaptic Zn21 signaling, this article summarizes involvement of intracellular Zn21 signaling in zincergic synapses in cognition. In nonzincergic synapses, furthermore, a hypothetical involvement of intracellular Zn21 signaling is described in relation to cognition. SYNAPTIC ZN21 LEVELS The basal Zn21 concentrations are extremely low in both the extracellular (1028 M; Frederickson et al., 2006) and the intracellular (cytosol;
Mini-Review Intracellular Zn21 Signaling in Cognition Atsushi Takeda,1,2* Hiroaki Fujii,2 Tatsuya Minamino,1 and Haruna Tamano1 1
Department of Bioorganic Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan 2 Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
Brain zinc homeostasis is strictly controlled under healthy conditions, indicating the importance of zinc for physiological function in the brain. A part of zinc in the brain exists in the synaptic vesicles, is released from a subclass of glutamatergic neurons (i.e., zincergic neurons), and serves as a signal factor (Zn21 signal) in the intracellular (cytosol) compartment as well as in the extracellular compartment. Zn21 signaling is dynamically linked to glutamate signaling and may be involved in synaptic plasticity, such as long-term potentiaion and cognitive activity. In zincergic synapses, intracellular Zn21 signaling in the postsynaptic neurons, which is linked to Zn21 release from zincergic neuron terminals, plays a role in cognitive activity. When nonzincergic synapses participate in cognition, on the other hand, it is possible that intracellular Zn21 signaling, which is due mainly to Zn21 release from the internal stores and/or metallothioneins, also is involved in cognitive activity, because zinc-dependent system such as zinc-binding proteins is usually required for cognitive process. Intracellular Zn21 dynamics may be modified via an endocrine system activity, glucocorticoid secretion in both zincergic and nonzincergic neurons, which is linked to a long-lasting change in synaptic efficacy. On the basis of the evidence of cognitive decline caused by the lack and/or the blockade of synaptic Zn21 signaling, this article summarizes the involvement of intracellular Zn21 signaling in zincergic synapses in cognition and a hypothetical involvement of that in nonzincergic synapses. VC 2014 Wiley Periodicals, Inc. Key words: Zn21 signal; cognition; hippocampus; glucocorticoid; glutamate
Zinc homeostasis is essential for human health (Maret and Sandstead, 2008; Prasad, 2012, 2013). The regulation of zinc homeostasis in the living body is tightly controlled by both intestinal absorption and intestinal and renal excretions (King et al., 2000). Zrt-Irt-like proteins (ZIP), which are responsible for the movement of zinc into the cytoplasm, and the zinc transporter (ZnT) family, which is responsible for the transport of zinc out of the cytoplasm, are involved in the absorption and excretion of zinc to maintain zinc homeostasis in the living body C 2014 Wiley Periodicals, Inc. V
(Fukada and Kambe, 2011). Serum zinc is thought to be a major pool of zinc in the living body to transfer zinc to the tissues and organs. On the other hand, brain zinc homeostasis is also strictly controlled under healthy conditions, indicating the importance of zinc for functioning in the brain and for brain development (Burdette and Lippard, 2003; Georgieff, 2007; Takeda and Tamano, 2009). Approximately 80% of total brain zinc exists as zinc metalloproteins. The residual zinc amount is histochemically reactive as revealed by Timm’s sulfide-silver staining method (Frederickson 1989; Frederickson and Danscher, 1990), because the lack of ZnT3 protein, which is responsible for the movement of zinc from the cytoplasm into the synaptic vesicles, results in a 20% reduction of the total amount of brain zinc (Palmiter et al., 1996; Cole et al., 1999). Although the chemical form of zinc in the synaptic vesicles is unknown, vesicular zinc composes a major pool for intracellular Zn21 signaling (Takeda et al., 2013). On the other hand, Zn21 levels, except for vesicular Zn21, are estimated to be less than 5% of the total Zn21 amount in the hippocampus and cerebral cortex (Lee et al., 2011). Zn21 is released with glutamate from a subclass of glutamatergic neurons, i.e., zincergic neurons, in the brain and modulates zincergic synapse activity (Frederickson 1989; Frederickson and Danscher, 1990). The hippocampus and amygdala are enriched with zincergic synapses. Synaptic Zn21 signaling may be linked to cognitive and emotional behavior (Takeda, 2010, 2011). Therefore, the spatiotemporal role of synaptic Zn21 signaling in the hippocampus and amygdala is important for understanding cognitive and emotional behavior. Synaptic plasticity, such as long-term-potentiation (LTP), is believed to be a cellular mechanism in memory *Correspondence to: Atsushi Takeda, Department of Bioorganic Chemistry &Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422–8526, Japan. E-mail: [email protected] Received 18 December 2013; Revised 30 January 2014; Accepted 21 February 2014 Published online 10 April 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jnr.23385
820
Takeda et al.
Fig. 1. Static Zn21 imaging in the hippocampus. Intracellular and extracellular Zn21 levels are imaged with ZnAF-2DA (left) and ZnAF-2 (right). The fluorescence is strongly observed in the hilus (H) and the stratum lucidam (SL).
and has been widely studied at glutamatergic synapses in the brain, especially in the hippocampus. Glutamatergic neurons compose neural circuits in the hippocampus and amygdala to process the information in memory. On the other hand, it is well known that hypothalamic-pituitaryadrenal (HPA) axis activity, i.e., glucocorticoid secretion, can potentiate glutamatergic neuron activity (Sandi, 2011) and that HPA axis activity is critical not only for cognitive behavior but also for emotional behavior (Howland and Wang, 2008; Jo€els and Karst, 2012). Glucocorticoid signaling may modify synaptic Zn21 signaling and is linked to cognitive and emotional behavior (Takeda and Tamano, 2012). On the basis of the evidence of cognitive decline caused by the lack and/or the blockade in synaptic Zn21 signaling, this article summarizes involvement of intracellular Zn21 signaling in zincergic synapses in cognition. In nonzincergic synapses, furthermore, a hypothetical involvement of intracellular Zn21 signaling is described in relation to cognition. SYNAPTIC ZN21 LEVELS The basal Zn21 concentrations are extremely low in both the extracellular (1028 M; Frederickson et al., 2006) and the intracellular (cytosol;
