Deletion of glycine transporter 1 (GlyT1) in forebrain neurons facilitates reversal learning: Enhanced cognitive adaptability?

Singer, Philipp; Boison, Detlev; Möhler, Hanns; Feldon, Joram; Yee, Benjamin K.

doi:10.1037/a0016676

Cited by 24 publications

(28 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our finding of enhanced reversal learning, without disrupting acquisition during water-maze testing, is reminiscent of the impaired reversal learning phenotype in mutant mice with glutamatergic signaling deficiency including mGlu 5 R (Xu et al 2009), NMDA receptor subunit NR2A (Bannerman et al 2008), and AMPA receptor subunit GluR-A (Bannerman et al 2003) knockout mice and of the enhanced phenotype in forebrain neuron-specific glycine transporter (GlyT1) knockout mice (Singer et al 2009). These gene knockout studies suggest that the potentiation of glutamatergic and/or NMDAR-mediated signaling may be linked to the enhancement of reversal learning.…”

Section: Selective Inactivation Of Striatal Neuronal a 2a Rs Enhancesmentioning

confidence: 99%

See 1 more Smart Citation

Selective inactivation of adenosine A_2A receptors in striatal neurons enhances working memory and reversal learning

Wei¹,

Singer²,

Coelho³

et al. 2011

Learn. Mem.

Self Cite

View full text Add to dashboard Cite

The adenosine A 2A receptor (A 2A R) is highly enriched in the striatum where it is uniquely positioned to integrate dopaminergic, glutamatergic, and other signals to modulate cognition. Although previous studies support the hypothesis that A 2A R inactivation can be pro-cognitive, analyses of A 2A R's effects on cognitive functions have been restricted to a small subset of cognitive domains. Furthermore, the relative contribution of A 2A Rs in distinct brain regions remains largely unknown. Here, we studied the regulation of multiple memory processes by brain region-specific populations of A 2A Rs. Specifically, we evaluated the cognitive impacts of conditional A 2A R deletion restricted to either the entire forebrain (i.e., cerebral cortex, hippocampus, and striatum, fb-A 2A R KO) or to striatum alone (st-A 2A R KO) in recognition memory, working memory, reference memory, and reversal learning. This comprehensive, comparative analysis showed for the first time that depletion of A 2A R-dependent signaling in either the entire forebrain or striatum alone is associated with two specific phenotypes indicative of cognitive flexibility-enhanced working memory and enhanced reversal learning. These selective pro-cognitive phenotypes seemed largely attributed to inactivation of striatal A 2A Rs as they were captured by A 2A R deletion restricted to striatal neurons. Neither spatial reference memory acquisition nor spatial recognition memory were grossly affected, and no evidence for compensatory changes in striatal or cortical D 1 , D 2 , or A 1 receptor expression was found. This study provides the first direct demonstration that targeting striatal A 2A Rs may be an effective, novel strategy to facilitate cognitive flexibility under normal and pathologic conditions.

show abstract

Section: Selective Inactivation Of Striatal Neuronal a 2a Rs Enhancesmentioning

confidence: 99%

“…The apparatus has been fully described before (Yee et al 2007;Singer et al 2009). Three tests were conducted: visible cue task, working memory task, and acquisition and reversal of reference memory.…”

Section: Water Mazementioning

confidence: 99%

Selective inactivation of adenosine A_2A receptors in striatal neurons enhances working memory and reversal learning

Wei¹,

Singer²,

Coelho³

et al. 2011

Learn. Mem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…This can be effectively achieved by pharmacological inhibition of glycine re-uptake via glycine transporter 1 (GlyT1) which co-localizes with NMDARs in neurons. Such inhibition has been reported to enhance NMDAR excitability, confer resistance to behavioral deficits induced by NMDAR antagonists, and lead to some forms of enhanced cognitive performance (Black et al , 2009; Depoortere et al , 2005; Singer, Boison, Mohler, Feldon, & Yee, 2009). …”

Section: Introductionmentioning

confidence: 99%

Impacts of forebrain neuronal glycine transporter 1 disruption in the senescent brain: Evidence for age-dependent phenotypes in Pavlovian learning.

Dubroqua¹,

Singer²,

Boison³

et al. 2010

Behavioral Neuroscience

Self Cite

View full text Add to dashboard Cite

Genetic deletion of glycine transporter 1 (GlyT1) in forebrain neurons gives rise to multiple procognitive phenotypes, presumably due to enhanced N-methyl-D-aspartate receptor (NMDAR) functions. However, concerns over possible harmful excitotoxic effects under life-long elevation of synaptic glycine have been raised. Such effects might accelerate the aging process, weakening or even reversing the pro-cognitive phenotypes identified in adulthood. Here, we examined if one of the most robust phenotypes in the mutant mouse line (CamKIIαCre;GlyT1tm1.2fl/fI), namely, enhanced aversive Pavlovian conditioning, might be modified by age. Comparison between 3-month-old (adult) and 22-month-old (aged) mutants confirmed the presence of this phenotype at both ages. However, the temporal expression of the Pavlovian phenotype was modified in senescence; while adult mutants showed a pronounced within-session extinction, aged mutants did not. Expression of NR2B subunits of NMDAR and neural proliferation were examined in the same animals by immunohistochemistry. These were reduced in the aged mice as expected, but not exacerbated by the mutation. Thus, our results do not substantiate the concerns of neurotoxic effects through life-long GlyT1 disruption in forebrain neurons, but provide evidence for a modification of phenotypic expression as a function of age. The latter points raise the need to further investigate other pro-cognitive phenotypes identified at adulthood in this mutant line. In addition, we revealed here for the first time a clear increase in the number of immature neurons in the hippocampus of the mutants, although the behavioral significance of this phenotype remains to be determined.

show abstract

“…A detailed description of the apparatus and procedure has been provided elsewhere (Singer, Boison, Möhler, Feldon, & Yee, 2009a). On the first day, the animals were pre-trained using a visually Bcued^platform in order to familiarize them to swimming in the pool and climbing onto the platform.…”

Section: Spatial Reference Memory and New Learning In The Water Mazementioning

confidence: 99%

Individual difference in prepulse inhibition does not predict spatial learning and memory performance in C57BL/6 mice

Peleg‐Raibstein

Singer

Feldon

et al. 2015

Cogn Affect Behav Neurosci

Self Cite

View full text Add to dashboard Cite

The startle reflex to an intense acoustic pulse stimulus is attenuated if the pulse stimulus is shortly preceded by a weak non-startling prepulse stimulus. This attenuation of the startle reflex represents a form of pre-attentional sensory gating known as prepulse inhibition (PPI). Although PPI does not require learning, its expression is regulated by higher cognitive processes. PPI deficits have been detected in several psychiatric conditions including schizophrenia where they coexist with cognitive deficits. A potential link between PPI expression and cognitive performance has therefore been suggested such that poor PPI may predict, or may be mechanistically linked to, overt cognitive impairments. A positive relationship between PPI and strategy formation, planning efficiency, and execution speed has been observed in healthy humans. However, parallel studies in healthy animals are rare. It thus remains unclear what cognitive domains may be associated with, or orthogonal to, sensory gating in the form of PPI in healthy animals. The present study evaluated a potential link between the magnitude of PPI and spatial memory performance by comparing two subgroups of animals differing substantially in baseline PPI expression (low-PPI vs high-PPI) within a homogenous cohort of 100 male adult C57BL/6 mice. Assessment of spatial reference memory in the Morris water maze and spatial recognition memory in the Y-maze failed to reveal any difference between low-PPI and high-PPI subjects. These negative findings contrast with our previous reports that individual difference in PPI correlated with sustained attention and working memory performance in C57BL/6 mice.

show abstract

Deletion of glycine transporter 1 (GlyT1) in forebrain neurons facilitates reversal learning: Enhanced cognitive adaptability?

Cited by 24 publications

References 45 publications

Selective inactivation of adenosine A_2A receptors in striatal neurons enhances working memory and reversal learning

Selective inactivation of adenosine A_2A receptors in striatal neurons enhances working memory and reversal learning

Impacts of forebrain neuronal glycine transporter 1 disruption in the senescent brain: Evidence for age-dependent phenotypes in Pavlovian learning.

Individual difference in prepulse inhibition does not predict spatial learning and memory performance in C57BL/6 mice

Contact Info

Product

Resources

About

Deletion of glycine transporter 1 (GlyT1) in forebrain neurons facilitates reversal learning: Enhanced cognitive adaptability?

Cited by 24 publications

References 45 publications

Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning

Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning

Impacts of forebrain neuronal glycine transporter 1 disruption in the senescent brain: Evidence for age-dependent phenotypes in Pavlovian learning.

Individual difference in prepulse inhibition does not predict spatial learning and memory performance in C57BL/6 mice

Contact Info

Product

Resources

About

Selective inactivation of adenosine A_2A receptors in striatal neurons enhances working memory and reversal learning

Selective inactivation of adenosine A_2A receptors in striatal neurons enhances working memory and reversal learning