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

Karin Nordenankar,Jana Mejia-Toiber,Carolina Birgner,Åsa Wallén-Mackenzie,Casey J A Smith-Anttila,Nadine Schweizer,Richardson N Leao,Marisela Morales,Thomas Viereckel

doi:10.1007/s00429-014-0778-9

Karin Nordenankar, Jana Mejia-Toiber + Show 7 more

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https://doi.org/10.1007/s00429-014-0778-9

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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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-014-0778-9) contains supplementary material, which is available to authorized users.

Highlights

The A10 area of the ventral midbrain is the home of the classical dopamine (DA) neurons that are important for motivation, reward, learning and memory via substantial projections into limbic and cognitive regions
The present study focused on investigating the function of vesicular glutamate transporter 2 (Vglut2) expression in neurons that either transiently or stably express tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine synthesis
We found that the targeted deletion of Vglut2 in TH-expressing neurons resulted in a memory formation-deficit observed as an increased time required to acquire hippocampus-dependent spatial memory and elevated amount of errors produced in the radial arm maze, a finding which could possibly be associated with the observations of decreased DA levels and altered firing pattern in CA3 neurons of the hippocampus

Summary

Introduction

The A10 area of the ventral midbrain is the home of the classical dopamine (DA) neurons that are important for motivation, reward, learning and memory via substantial projections into limbic and cognitive regions. Three distinct neuronal populations expressing the vesicular glutamate transporter 2 (Vglut, aka Slc17A6) gene, which confers a glutamatergic phenotype (Fremeau et al 2004), have been identified within the VTA of the adult rat and mouse Of these three VTA Vglut2-expressing (VTA-VGLUT2) populations, one appears to consist of purely glutamatergic neurons (‘‘Glu-only’’ or ‘‘Vglut2-only’’) that show similar electrophysiological properties and projections as the neighbouring DA neurons (Hnasko et al 2012; Kawano et al 2006; Yamaguchi et al 2007). The functional role of Vglut expression in DA neurons has been investigated by different laboratories using the Cre-LoxP-based conditional knockout technique (Wallen-Mackenzie et al 2010) targeting DA neurons via DAT promoter-driven expression of Cre recombinase Summarized, these studies demonstrated that DATCre-mediated deletion of Vglut expression left motivation and memory parameters intact, while causing altered responses to sweet food and psychostimulants, thereby revealing a role for the glutamate-DA cophenotype in certain aspects of reward processing We used behavioural, electrochemical and electrophysiological techniques to analyse this new conditional Vglut knockout mouse

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