Abstract
Glutamate delta-1 (GluD1) receptors are expressed throughout the forebrain during development with high levels in the hippocampus during adulthood. We have recently shown that deletion of GluD1 receptor results in aberrant emotional and social behaviors such as hyperaggression and depression-like behaviors and social interaction deficits. Additionally, abnormal expression of synaptic proteins was observed in amygdala and prefrontal cortex of GluD1 knockout mice (GluD1 KO). However the role of GluD1 in learning and memory paradigms remains unknown. In the present study we evaluated GluD1 KO in learning and memory tests. In the eight-arm radial maze GluD1 KO mice committed fewer working memory errors compared to wildtype mice but had normal reference memory. Enhanced working memory in GluD1 KO was also evident by greater percent alternation in the spontaneous Y-maze test. No difference was observed in object recognition memory in the GluD1 KO mice. In the Morris water maze test GluD1 KO mice showed no difference in acquisition but had longer latency to find the platform in the reversal learning task. GluD1 KO mice showed a deficit in contextual and cue fear conditioning but had normal latent inhibition. The deficit in contextual fear conditioning was reversed by D-Cycloserine (DCS) treatment. GluD1 KO mice were also found to be more sensitive to foot-shock compared to wildtype. We further studied molecular changes in the hippocampus, where we found lower levels of GluA1, GluA2 and GluK2 subunits while a contrasting higher level of GluN2B in GluD1 KO. Additionally, we found higher postsynaptic density protein 95 (PSD95) and lower glutamate decarboxylase 67 (GAD67) expression in GluD1 KO. We propose that GluD1 is crucial for normal functioning of synapses and absence of GluD1 leads to specific abnormalities in learning and memory. These findings provide novel insights into the role of GluD1 receptors in the central nervous system.
Highlights
The delta family of ionotropic glutamate receptors has two members glutamate delta 1 (GluD1) and glutamate delta 2 (GluD2) receptors, which share,60% homology between themselves
We found that GluD1 KO have enhanced working memory in the radial maze and Y-maze alternation test, a deficit in reversal learning in the Morris water maze test and a deficit in contextual and cue fear conditioning
We have previously demonstrated that GluD1 deletion leads to abnormalities in synaptic proteins in the prefrontal cortex and amygdala [16]
Summary
The delta family of ionotropic glutamate receptors (iGluRs) has two members glutamate delta 1 (GluD1) and glutamate delta 2 (GluD2) receptors, which share ,60% homology between themselves. We recently demonstrated for the first time that GluD1 knockout mice (GluD1 KO) exhibit deficits in emotional and social behaviors [16]. These behaviors were highlighted by lower anxiety-like behavior, hyperaggression, higher depressionlike behavior and deficits in social interaction. This behavioral phenotype in GluD1 KO mimics certain features of GluD1 associated neuropsychiatric disorders. A previous study has demonstrated that GluD1 KO show no deficit in spatial learning in a Morris water maze test [2] it is not fully understood whether GluD1 deletion may affect other forms of learning and memory
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