Dopamine D2R is Required for Hippocampal-dependent Memory and Plasticity at the CA3-CA1 Synapse

Abstract

Dopamine receptors play an important role in motivational, emotional, and motor responses. In addition, growing evidence suggests a key role of hippocampal dopamine receptors in learning and memory. It is well known that associative learning and synaptic plasticity of CA3-CA1 requires the dopamine D1 receptor (D1R). However, the specific role of the dopamine D2 receptor (D2R) on memory-related neuroplasticity processes is still undefined. Here, by using two models of D2R loss, D2R knockout mice (Drd2−/−) and mice with intrahippocampal injections of Drd2-small interfering RNA (Drd2-siRNA), we aimed to investigate how D2R is involved in learning and memory as well as in long-term potentiation of the hippocampus. Our studies revealed that the genetic inactivation of D2R impaired the spatial memory, associative learning, and the classical conditioning of eyelid responses. Similarly, deletion of D2R reduced the activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. Our results demonstrate the first direct evidence that D2R is essential in behaving mice for trace eye blink conditioning and associated changes in hippocampal synaptic strength. Taken together, these results indicate a key role of D2R in regulating hippocampal plasticity changes and, in consequence, acquisition and consolidation of spatial and associative forms of memory.

Bidirectional Regulation of Hippocampal Synaptic Plasticity and Modulation of Cumulative Spatial Memory by Dopamine D2-Like Receptors

“…Our results in the episodic-like task and the cumulative semantic-like paradigm both showed that the rats performed worse in recognizing novel features of the objects in the presence of the D2R antagonist, compared to controls, during the final test sessions. These findings in rats align with reports from behavioral studies in mice in which D2R were either knocked-out or silenced specifically in the CA1 region, which demonstrated that spatial working memory (Glickstein et al, 2002), spatial and recognition learning and memory (Rocchetti et al, 2015), reversal learning and even associative learning, such as in trace eyeblink conditioning (Espadas et al, 2021) are all impaired when D2R function is disrupted. Others have reported that D2R-antagonism can affect movement initiation and execution (Amalric et al, 1993;Hauber, 1996;Parr-Brownlie and Hyland, 2005).…”

“…However, it has been reported that these receptors are not required for mossy fiber LTP or LTD in the CA3 region in vivo (Hagena and Manahan-Vaughan, 2016 ), whereas in the dentate gyrus (DG), receptor antagonism prevents weak but not strong forms of LTP in behaving rats (Manahan-Vaughan and Kulla, 2003 ). Mice lacking D2R also show reduced LTP (Espadas et al, 2021 ). D2R activation in the hippocampus has been reported to lower excitability levels and, thus, raises the threshold for induction of LTP (Manahan-Vaughan and Kulla, 2003 ).…”

Constitutive gene expression differs in three brain regions important for cognition in neophobic and non-neophobic house sparrows (Passer domesticus)

“…Indeed, submitted work from our lab examining immediate early gene activity in neophobic and non-neophobic birds demonstrates that both phenotypes show a similar increase in neuronal activity in the AMV response to novel objects compared to non-object controls [79]. Intriguingly, some of the most highly differentially expressed genes between neophobic and non-neophobic individuals include important known neuroendocrine mediators of learning, memory, executive function, and anxiety behavior, including serotonin receptor 5A, dopamine receptors 1, 2 and 5, and estrogen receptor beta [80][81][82][83][84]. Behavioral variation has been associated with differential receptor density and gene expression in specific neuromodulatory systems in several species.…”

Cannabinoid control of hippocampal functions: the where matters

“…These neurons control the late stages of novel object recognition (NOR) memory by facilitating learning-induced long-term potentiation (LTP) [36]. The dopaminergic system participates in memory consolidation [37], and particularly, in the coding of novel experiences [38]. Intriguingly, the study of these neurons also suggests that there is a dopaminergic regulation that underlies cannabinergic signaling and memory consolidation.…”