Delayed-matching-to-position working memory in mice relies on NMDA-receptors in prefrontal pyramidal cells

Abstract

A hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs) has been implicated in the pathogenesis of schizophrenia by clinical and rodent studies. However, to what extent NMDAR-hypofunction in distinct cell-types across the brain causes different symptoms of this disease is largely unknown. One pharmaco-resistant core symptom of schizophrenia is impaired working memory (WM). NMDARs have been suggested to mediate sustained firing in excitatory neurons of the prefrontal cortex (PFC) that might underlie WM storage. However, if NMDAR-hypofunction in prefrontal excitatory neurons may indeed entail WM impairments is unknown. We here investigated this question in mice, in which NMDARs were genetically-ablated in PFC excitatory cells. This cell type-selective NMDAR-hypofunction caused a specific deficit in a delayed-matching-to-position (DMTP) 5-choice-based operant WM task. In contrast, T-maze rewarded alternation and several psychological functions including attention, spatial short-term habituation, novelty-processing, motivation, sociability, impulsivity, and hedonic valuation remained unimpaired at the level of GluN1-hypofunction caused by our manipulation. Our data suggest that a hypofunction of NMDARs in prefrontal excitatory neurons may indeed cause WM impairments, but are possibly not accounting for most other deficits in schizophrenia.

Distinct contributions of GluA1-containing AMPA receptors of different hippocampal subfields to salience processing, memory and impulse control

“…Subgroup sizes were chosen according to our previous data in the respective behavioural tests [ 39 – 41 ]. Surgery was conducted as described previously [ 40 ] and in Supplementary Methods. Mice were housed in individually ventilated cages (IVC) containing sawdust, sizzle nest and one cardboard ‘house’ (Datesand, UK) as enrichment, throughout.…”

Apparatus design and behavioural testing protocol for the evaluation of spatial working memory in mice through the spontaneous alternation T-maze

“…Finally, T-mazes and Y-mazes can be utilized also to assess short-term habituation to a novel environment 49 – 56 . Basically, animals are exposed for a determined amount of time (for example 15 min) to a training session with one arm closed and two open.…”

A low-cost open-source 5-choice operant box system optimized for electrophysiology and optophysiology in mice

“…5 a and Supplementary Video 2 for an illustration of the task). As light levels and colour of 5-choice wall stimuli vary greatly between commercial systems (we have previously used defaults of 215 lx white light in one system (Campden Instruments Ltd. 25 ) and 4 lx of yellow light in another (Med Associates Inc. 19 , 23 , 24 ), we started with a high illumination of 280 lx of white light as measured in front of the poke-holes. We observed qualitatively that some animals would refrain from poking into the hole even when sitting right in front of them and that no training progress was evident over 4 days as assessed by repeated-measures (RM) ANOVA (Supplementary Fig.…”

“…This is critical, for example, when assessing sustained attention in the 5-CSRTT to demand a spatially broad focus of attention and to prevent a strategy of obtaining sufficient rewards just from near-chance level performance 13 . Similarly in the 5-CSWMT this allows presentation of a large number of different two-hole or multi-hole choice configurations in the choice phase to prevent mediation strategies of positioning the body in one side of the chamber to solve the task without memory (discussed in more detail elsewhere 12 , 24 ). Therefore, the wide applicability of the 5-poke design to assess a considerable number of cognitive functions is the key source of versatility offered by the pyOS-5 boxes.…”

“…The training of cohort 5 in the 5-CSWMT is described in detail elsewhere 21 , as is comparable data from the same task acquired in commercial boxes 12 , 24 . Briefly, each trial of this delayed-matching-to-position (DMTP) spatial working memory assay consists of a sample phase (SP) during which the mice have to detect and poke an illuminated hole (as in the 5-CSRTT), a delay phase during which mice obtain a small reward from the receptacle (10 µl strawberry milk), and the choice phase (CP) during which mice are presented with two illuminated holes at the 5-choice wall (see illustration of task cycle in Supplementary Fig.…”