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Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity.

Nordenankar K, Smith-Anttila CJ, Schweizer N, Viereckel T, Birgner C, Mejia-Toiber J, Morales M, Leao RN, Wallén-Mackenzie Å - Brain Struct Funct (2014)

Bottom Line: The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout.Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus.In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area.

View Article: PubMed Central - PubMed

Affiliation: Unit of Functional Neurobiology and Unit of Developmental Genetics, Biomedical Center, Department of Neuroscience, Uppsala University, Box 593, S-751 24, Uppsala, Sweden.

ABSTRACT
Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations ("TH-Vglut2 Class1") also expressed the dopamine transporter (DAT) gene while one did not ("TH-Vglut2 Class2"), and the remaining population did not express TH at all ("Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area.

No MeSH data available.


HPLC analysis of DA and its metabolites in dissected brain material. Tissue content of dopamine (DA), 3,4-Dihydroxyphenyl-acetic acid (DOPAC) and homovanillic acid (HVA) of control (white bars) and cKO (grey bars) mice, all in ng/g wet tissue. Olfactory bulb (a); substantia nigra pars compacta/Ventral tegmental area (SNc/VTA) (b); hypothalamus (c); nucleus accumbens (NAcc) (d); caudate putamen (CAPu) (e); prefrontal cortex (f); amygdala (g); hippocampus (h). Single asteriskp < 0.05; doubleasterisk p < 0.001 (Mann–Whitney U test)
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Fig6: HPLC analysis of DA and its metabolites in dissected brain material. Tissue content of dopamine (DA), 3,4-Dihydroxyphenyl-acetic acid (DOPAC) and homovanillic acid (HVA) of control (white bars) and cKO (grey bars) mice, all in ng/g wet tissue. Olfactory bulb (a); substantia nigra pars compacta/Ventral tegmental area (SNc/VTA) (b); hypothalamus (c); nucleus accumbens (NAcc) (d); caudate putamen (CAPu) (e); prefrontal cortex (f); amygdala (g); hippocampus (h). Single asteriskp < 0.05; doubleasterisk p < 0.001 (Mann–Whitney U test)

Mentions: The VGLUT2 protein has been suggested to play a role in DA transmission by affecting vesicular packaging of DA by a process termed “vesicular synergy”, a concept which postulates that a VGLUT may work in synergy with another vesicular transporter, such as the monoamine transporter VMAT2, to increase the efficiency of this transporter (Gras et al. 2008). We and others have previously shown that loss of VGLUT2 in DA neurons in the Vglut2f/f;DAT-Cre mouse line leads to decreased DA release, possibly, but not conclusively, supporting the concept of vesicular synergy between VGLUT2 and VMAT2 (Alsiö et al. 2011; Hnasko et al. 2010). To assess if the targeted loss of VGLUT2 would affect DA levels in the Vglut2f/f;TH-Cre mouse line, HPLC was used to assess possible differences in the concentration of DA as well as its metabolites DOPAC and HVA in cKO and control mice. This analysis was carried out in a number of different brain regions, including the VTA/SNc area, the olfactory bulb and the hypothalamus, all of which contain DA neuronal cell bodies, as well as the nucleus accumbens (NAcc), caudate putamen (CaPu), prefrontal cortex (PFC), amygdala and the hippocampus as these regions are known target areas of DA neurons. No difference was observed in DA, DOPAC or HVA concentrations in the olfactory bulb, VTA/SNc, CaPu, NAcc, hypothalamus or the PFC between cKO and littermate control mice (Fig. 6a–f). However, a significant increase was observed in DOPAC concentration in the amygdala of cKO mice in comparison to controls (p = 0.0426), but not in DA or HVA (Fig. 6g). In contrast, the concentration of DA (p = 0.0311), DOPAC (p = 0.0489) and HVA (p = 0.0022) was all significantly reduced in the hippocampus of cKO mice in comparison to littermate controls (Fig. 4h).Fig. 6


Increased hippocampal excitability and impaired spatial memory function in mice lacking VGLUT2 selectively in neurons defined by tyrosine hydroxylase promoter activity.

Nordenankar K, Smith-Anttila CJ, Schweizer N, Viereckel T, Birgner C, Mejia-Toiber J, Morales M, Leao RN, Wallén-Mackenzie Å - Brain Struct Funct (2014)

HPLC analysis of DA and its metabolites in dissected brain material. Tissue content of dopamine (DA), 3,4-Dihydroxyphenyl-acetic acid (DOPAC) and homovanillic acid (HVA) of control (white bars) and cKO (grey bars) mice, all in ng/g wet tissue. Olfactory bulb (a); substantia nigra pars compacta/Ventral tegmental area (SNc/VTA) (b); hypothalamus (c); nucleus accumbens (NAcc) (d); caudate putamen (CAPu) (e); prefrontal cortex (f); amygdala (g); hippocampus (h). Single asteriskp < 0.05; doubleasterisk p < 0.001 (Mann–Whitney U test)
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Related In: Results  -  Collection

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Fig6: HPLC analysis of DA and its metabolites in dissected brain material. Tissue content of dopamine (DA), 3,4-Dihydroxyphenyl-acetic acid (DOPAC) and homovanillic acid (HVA) of control (white bars) and cKO (grey bars) mice, all in ng/g wet tissue. Olfactory bulb (a); substantia nigra pars compacta/Ventral tegmental area (SNc/VTA) (b); hypothalamus (c); nucleus accumbens (NAcc) (d); caudate putamen (CAPu) (e); prefrontal cortex (f); amygdala (g); hippocampus (h). Single asteriskp < 0.05; doubleasterisk p < 0.001 (Mann–Whitney U test)
Mentions: The VGLUT2 protein has been suggested to play a role in DA transmission by affecting vesicular packaging of DA by a process termed “vesicular synergy”, a concept which postulates that a VGLUT may work in synergy with another vesicular transporter, such as the monoamine transporter VMAT2, to increase the efficiency of this transporter (Gras et al. 2008). We and others have previously shown that loss of VGLUT2 in DA neurons in the Vglut2f/f;DAT-Cre mouse line leads to decreased DA release, possibly, but not conclusively, supporting the concept of vesicular synergy between VGLUT2 and VMAT2 (Alsiö et al. 2011; Hnasko et al. 2010). To assess if the targeted loss of VGLUT2 would affect DA levels in the Vglut2f/f;TH-Cre mouse line, HPLC was used to assess possible differences in the concentration of DA as well as its metabolites DOPAC and HVA in cKO and control mice. This analysis was carried out in a number of different brain regions, including the VTA/SNc area, the olfactory bulb and the hypothalamus, all of which contain DA neuronal cell bodies, as well as the nucleus accumbens (NAcc), caudate putamen (CaPu), prefrontal cortex (PFC), amygdala and the hippocampus as these regions are known target areas of DA neurons. No difference was observed in DA, DOPAC or HVA concentrations in the olfactory bulb, VTA/SNc, CaPu, NAcc, hypothalamus or the PFC between cKO and littermate control mice (Fig. 6a–f). However, a significant increase was observed in DOPAC concentration in the amygdala of cKO mice in comparison to controls (p = 0.0426), but not in DA or HVA (Fig. 6g). In contrast, the concentration of DA (p = 0.0311), DOPAC (p = 0.0489) and HVA (p = 0.0022) was all significantly reduced in the hippocampus of cKO mice in comparison to littermate controls (Fig. 4h).Fig. 6

Bottom Line: The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout.Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus.In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area.

View Article: PubMed Central - PubMed

Affiliation: Unit of Functional Neurobiology and Unit of Developmental Genetics, Biomedical Center, Department of Neuroscience, Uppsala University, Box 593, S-751 24, Uppsala, Sweden.

ABSTRACT
Three populations of neurons expressing the vesicular glutamate transporter 2 (Vglut2) were recently described in the A10 area of the mouse midbrain, of which two populations were shown to express the gene encoding, the rate-limiting enzyme for catecholamine synthesis, tyrosine hydroxylase (TH).One of these populations ("TH-Vglut2 Class1") also expressed the dopamine transporter (DAT) gene while one did not ("TH-Vglut2 Class2"), and the remaining population did not express TH at all ("Vglut2-only"). TH is known to be expressed by a promoter which shows two phases of activation, a transient one early during embryonal development, and a later one which gives rise to stable endogenous expression of the TH gene. The transient phase is, however, not specific to catecholaminergic neurons, a feature taken to advantage here as it enabled Vglut2 gene targeting within all three A10 populations expressing this gene, thus creating a new conditional knockout. These knockout mice showed impairment in spatial memory function. Electrophysiological analyses revealed a profound alteration of oscillatory activity in the CA3 region of the hippocampus. In addition to identifying a novel role for Vglut2 in hippocampus function, this study points to the need for improved genetic tools for targeting of the diversity of subpopulations of the A10 area.

No MeSH data available.