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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.


Analysis of basal and amphetamine-induced locomotion and of spatial memory. Horizontal locomotion (recorded as at least two consecutive photobeam interruptions) before and after saline- (a) and amphetamine- (b) injections; shown 30 minutes prior to injection (−30 to −10), injection indicated by time point 0, and 90 min post-injection (10–90) in 10 min intervals. Spatial memory testing in the baited radial arm maze. Schematic drawing of the maze depicting a correct choice (left), a reference memory error (RME) (middle) and a working memory error (WME) (right) (see materials and methods for details) (c). Performance of the mice during the acquisition days (1–5) and retention testing (day 23) as indicated by the number of correct choices (left), RMEs (middle) and WMEs (right) (d). Single asteriskp < 0.05; doubleasteriskp < 0.001(2-way ANOVA)
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Fig5: Analysis of basal and amphetamine-induced locomotion and of spatial memory. Horizontal locomotion (recorded as at least two consecutive photobeam interruptions) before and after saline- (a) and amphetamine- (b) injections; shown 30 minutes prior to injection (−30 to −10), injection indicated by time point 0, and 90 min post-injection (10–90) in 10 min intervals. Spatial memory testing in the baited radial arm maze. Schematic drawing of the maze depicting a correct choice (left), a reference memory error (RME) (middle) and a working memory error (WME) (right) (see materials and methods for details) (c). Performance of the mice during the acquisition days (1–5) and retention testing (day 23) as indicated by the number of correct choices (left), RMEs (middle) and WMEs (right) (d). Single asteriskp < 0.05; doubleasteriskp < 0.001(2-way ANOVA)

Mentions: The radial arm maze is a hippocampus-dependent task used to record spatial working memory (WM), in which the ability of the mouse to remember the location of food-baited versus unbaited arms is measured (Meck et al. 1984). Spatial memory performance was examined in 24 cKO mice and littermate controls, all males using an eight-armed radial maze (see Fig. 5 for illustration of the radial maze and the parameters scored). The maze, elevated 45 cm above the floor, consisted of eight open arms (60 cm long and 12.5 cm wide, surrounded by inclining walls at a height of 13 cm at the centre and 3 cm at the end of the maze arms) radiating from a central compartment (30 cm in diameter). A podium (10 × 4 cm) with a recessed food plate (diameter 3 cm) was fixed at 1.5 cm from the end of each of the maze arms. Three days prior to the beginning of the experiment, the mice were schedule-fed for 6 h/day, which was reduced to 2 h/day at the start of the behavioural studies. Four of the eight arms were baited with the preferred food, R6-38, consisting of a high content of theobroma cacao. For the acquisition period, the animals were placed individually in the centre of the maze once each day for 5 days. The animals were allowed to perform for 10 min on the first trial day and thereafter the animals were allowed to remain in the apparatus until all reinforcements were obtained or until 10 min had elapsed, whichever occurred first. The same four arms were baited with a small piece of reinforcement food pellet each day. Nineteen days after the last acquisition session a retention test was performed. The same arms were baited and the mice again the same procedure was followed. The mice were manually scored for performance during the trial time. For scoring, an entry half way into an arm was defined as an arm entry. For each trial, a reference memory error (RME) was defined as a visit into an unbaited or incorrect arm. A working memory error (WME) was defined as a re-entry into an arm in which the reward was already obtained during the session. The total number of entries into each arm and the percentage of correct responses were also scored. Results were analysed using StatView 5.0 for Windows. A 2 × 2 × 6 (genotype × sex × trial days) two-way repeated-measures ANOVA was used to assess RME, WME, total number of arm entries and the percentage of correct responses obtained during trial period. Test day was analysed by Student’s t test.


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)

Analysis of basal and amphetamine-induced locomotion and of spatial memory. Horizontal locomotion (recorded as at least two consecutive photobeam interruptions) before and after saline- (a) and amphetamine- (b) injections; shown 30 minutes prior to injection (−30 to −10), injection indicated by time point 0, and 90 min post-injection (10–90) in 10 min intervals. Spatial memory testing in the baited radial arm maze. Schematic drawing of the maze depicting a correct choice (left), a reference memory error (RME) (middle) and a working memory error (WME) (right) (see materials and methods for details) (c). Performance of the mice during the acquisition days (1–5) and retention testing (day 23) as indicated by the number of correct choices (left), RMEs (middle) and WMEs (right) (d). Single asteriskp < 0.05; doubleasteriskp < 0.001(2-way ANOVA)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig5: Analysis of basal and amphetamine-induced locomotion and of spatial memory. Horizontal locomotion (recorded as at least two consecutive photobeam interruptions) before and after saline- (a) and amphetamine- (b) injections; shown 30 minutes prior to injection (−30 to −10), injection indicated by time point 0, and 90 min post-injection (10–90) in 10 min intervals. Spatial memory testing in the baited radial arm maze. Schematic drawing of the maze depicting a correct choice (left), a reference memory error (RME) (middle) and a working memory error (WME) (right) (see materials and methods for details) (c). Performance of the mice during the acquisition days (1–5) and retention testing (day 23) as indicated by the number of correct choices (left), RMEs (middle) and WMEs (right) (d). Single asteriskp < 0.05; doubleasteriskp < 0.001(2-way ANOVA)
Mentions: The radial arm maze is a hippocampus-dependent task used to record spatial working memory (WM), in which the ability of the mouse to remember the location of food-baited versus unbaited arms is measured (Meck et al. 1984). Spatial memory performance was examined in 24 cKO mice and littermate controls, all males using an eight-armed radial maze (see Fig. 5 for illustration of the radial maze and the parameters scored). The maze, elevated 45 cm above the floor, consisted of eight open arms (60 cm long and 12.5 cm wide, surrounded by inclining walls at a height of 13 cm at the centre and 3 cm at the end of the maze arms) radiating from a central compartment (30 cm in diameter). A podium (10 × 4 cm) with a recessed food plate (diameter 3 cm) was fixed at 1.5 cm from the end of each of the maze arms. Three days prior to the beginning of the experiment, the mice were schedule-fed for 6 h/day, which was reduced to 2 h/day at the start of the behavioural studies. Four of the eight arms were baited with the preferred food, R6-38, consisting of a high content of theobroma cacao. For the acquisition period, the animals were placed individually in the centre of the maze once each day for 5 days. The animals were allowed to perform for 10 min on the first trial day and thereafter the animals were allowed to remain in the apparatus until all reinforcements were obtained or until 10 min had elapsed, whichever occurred first. The same four arms were baited with a small piece of reinforcement food pellet each day. Nineteen days after the last acquisition session a retention test was performed. The same arms were baited and the mice again the same procedure was followed. The mice were manually scored for performance during the trial time. For scoring, an entry half way into an arm was defined as an arm entry. For each trial, a reference memory error (RME) was defined as a visit into an unbaited or incorrect arm. A working memory error (WME) was defined as a re-entry into an arm in which the reward was already obtained during the session. The total number of entries into each arm and the percentage of correct responses were also scored. Results were analysed using StatView 5.0 for Windows. A 2 × 2 × 6 (genotype × sex × trial days) two-way repeated-measures ANOVA was used to assess RME, WME, total number of arm entries and the percentage of correct responses obtained during trial period. Test day was analysed by Student’s t test.

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.