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

Dopamine is a key factor in the enablement of cognition and hippocampal information processing. Its action in the hippocampus is mediated by D1/D5 and D2-like (D2, D3, D4) receptors. While D1/D5-receptors are well recognized as strong modulators of hippocampal synaptic plasticity and information storage, much less is known about the role of D2-like receptors (D2R) in these processes. Here, we explored to what extent D2R contribute to synaptic plasticity and cumulative spatial memory derived from semantic and episodic-like information storage. In freely behaving adult rats, we also assessed to what extent short and long-term forms of synaptic plasticity are influenced by pharmacological activation or blockade of D2R. Antagonism of D2R by means of intracerebral treatment with remoxipride, completely prevented the expression of both short-term (<1 h) and long-term potentiation (>4 h), as well as the expression of short-term depression (STD, <1 h) in the hippocampal CA1 region. Scrutiny of involvement of D2R in spatial learning revealed that D2R-antagonism prevented retention of a semantic spatial memory task, and also significantly impaired retention of recent spatiotemporal aspects of an episodic-like memory task. Taken together, these findings indicate that D2R are required for bidirectional synaptic plasticity in the hippocampal CA1 region. Furthermore, they are critically involved in enabling cumulative and episodic-like forms of spatial learning.

The Role of Hyperthermia in Methamphetamine-Induced Depression-Like Behaviors: Protective Effects of Coral Calcium Hydride

Methamphetamine (METH) abuse causes irreversible damage to the central nervous system and leads to psychiatric symptoms including depression. Notably, METH-induced hyperthermia is a crucial factor in the development of these symptoms, as it aggravates METH-induced neurotoxicity. However, the role of hyperthermia in METH-induced depression-like behaviors needs to be clarified. In the present study, we treated mice with different doses of METH under normal (NAT) or high ambient temperatures (HAT). We found that HAT promoted hyperthermia after METH treatment and played a key role in METH-induced depression-like behaviors in mice. Intriguingly, chronic METH exposure (10 mg/kg, 7 or 14 days) or administration of an escalating-dose (2 ∼ 15 mg/kg, 3 days) of METH under NAT failed to induce depression-like behaviors. However, HAT aggravated METH-induced damage of hippocampal synaptic plasticity, reaction to oxidative stress, and neuroinflammation. Molecular hydrogen acts as an antioxidant and anti-inflammatory agent and has been shown to have preventive and therapeutic applicability in a wide range of diseases. Coral calcium hydride (CCH) is a newly identified hydrogen-rich powder which produces hydrogen gas gradually when exposed to water. Herein, we found that CCH pretreatment significantly attenuated METH-induced hyperthermia, and administration of CCH after METH exposure also inhibited METH-induced depression-like behaviors and reduced the hippocampal synaptic plasticity damage. Moreover, CCH effectively reduced the activity of lactate dehydrogenase and decreased malondialdehyde, TNF-α and IL-6 generation in hippocampus. These results suggest that CCH is an efficient hydrogen-rich agent, which has a potential therapeutic applicability in the treatment of METH abusers.

Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review

Long-lasting changes of synaptic efficacy are largely mediated by activity-induced gene transcription and are essential for neuronal plasticity and memory. In this scenario, transcription factors have emerged as pivotal players underlying synaptic plasticity and the modification of neural networks required for memory formation and consolidation. Hippocampal synaptic dysfunction is widely accepted to underlie the cognitive decline observed in some neurodegenerative disorders including Alzheimer’s disease. Therefore, understanding the molecular pathways regulating gene expression profiles may help to identify new synaptic therapeutic targets. The nuclear receptor 4A subfamily (Nr4a) of transcription factors has been involved in a variety of physiological processes within the hippocampus, ranging from inflammation to neuroprotection. Recent studies have also pointed out a role for the activity-dependent nuclear receptor subfamily 4, group A, member 2 (Nr4a2/Nurr1) in hippocampal synaptic plasticity and cognitive functions, although the underlying molecular mechanisms are still poorly understood. In this review, we highlight the specific effects of Nr4a2 in hippocampal synaptic plasticity and memory formation and we discuss whether the dysregulation of this transcription factor could contribute to hippocampal synaptic dysfunction, altogether suggesting the possibility that Nr4a2 may emerge as a novel synaptic therapeutic target in brain pathologies associated to cognitive dysfunctions.