Hippocampal Synaptic Plasticity Mechanisms Underlying Emotional Memory

The hippocampus is the critical brain region involved in memory and emotion process, but the cellular and molecular mechanisms remain elusive. Since Tim Bliss found hippocampal long-term potentiation (LTP), the mechanism and function of synaptic plasticity in learning and memory have been intensively investigated. During LTP induction, increased glutamate release from presynaptic terminals activates postsynaptic NMDA receptors, which lead to calcium concentration increase. Calcium triggers the activation of signaling cascades, leading to LTP expression through AMPAR phosphorylation and insertion into postsynaptic membrane. Long-term depression (LTD) is another form of hippocampal synaptic plasticity, which has two distinct forms, i.e. NMDA receptor-dependent and independent. Both LTD trigger the intracelluar signaling cascades, commonly leading to AMPAR endocytosis and expression of LTD. Hippocampal LTP and LTD are believed to be the cellular and molecular mechanism that underlies the hippocampus-dependent learning and memory. However, it is not known whether synaptic plasticity is implicated in hippocampus-dependent emotion processing.Major depression is a common mental illness characterized by mood dysfunction and enhanced negative emotional memory. Previous evidence shows that the hippocampus is involved in pathogenesis of depression and in response to antidepressive treatment, but the underlying mechanisms are essentially unknown. Some psychoactive substances, such as ketamine and cannabinoids, have been popularly used for antidepression and analgesia at low doses. However, at high doses they can induce side effects, such as psychosis and memory impairment. The underlying mechanisms of memory impairment induced by ketamine and cannabinoids remain elusive.As the hippocampus is critical for emotion and memory, hippocampal synaptic plasticity may be their common mechanism. Electrophysiological recording technique in freely moving rats has many advantages, such as it is allowed long lasting observation, even for months in conscious and anaesthetic-free rats, and the neural circuitry is intact, etc. In our studies, in the first part, combining freely moving rat recording and learned despair model of depression (forced swimming test, FST), we investigated the effects of FST on hippocampal CA1synaptic transmission at the cellular and molecular levels, and the effects of interfering hippocampal synaptic plasticity on despair-like behaviors. Combining morris water maze, we studied the mechanisms of subanesthetic ketamine or cannabinoid-induced hippocampal CA1synaptic depression and memory impairment. In the second part, we also investigated the effects of CXZ-123a natural product that can rapidly exert antidepressive effect, on hippocampal synaptic transmission in freely moving rats.We found that forced swimming test, one of the most commonly used models to evaluate the antidepressant effects, induced endogenous LTP that lasted more than one hour. Pretreatment with NMDA receptor antagonist (AP-5) blocked the endogenous LTP, indicating that this endogenous LTP is NMDA receptor-dependent. The BDNF Trk receptor antagonist K252a and protein synthesis inhibitor anisomycin, which are known to impair LTP maintenance, also blocked the endogenous LTP and the learned despair behavior. Then, by applying deep brain stimulation in the hippocampus immediately after training produced the same effect. In freely moving rats, a small natural product CXZ-123induced long-term depression and blocked learned despair behavior. Thus, our data suggest that hippocampal LTP is implicated in the formation of learned despair behavior, a mechanism suggesting the development of depression.Next, we investigated the cellular and molecular mechanisms underlying memory impairment in schizophrenia-like animal model. We used subanesthetic ketamine-induced animal model of schizophrenia. Consistent with previous reports, we found that subanesthetic ketamine induced a series of schizophrenia-like symptoms. Ketamine induced long-term spatial memory impairment as assessed in the Morris water maze. The same dose of ketamine also produced synaptic depression lasting at least4hr at hippocampal Schaeffer collateral-CAl synapses in freely moving rats. The synaptic depression induced by ketamine is unlikely to depend on NMDA receptors but may depend on dopamine D1/D5receptors and AMPA receptors endocytosis. Pretreatment with the D1/D5receptors antagonist SCH23390or the AMPA receptors endocytosis interfering peptide Tat-GluR23Y blocked synaptic depression and spatial memory impairment induced by ketamine. Thus, our data indicate that dopamine D1/D5receptors may modulate AMPA receptors endocytosis, which plays a critical role in memory impairment induced by ketamine.We investigated the cellular and molecular mechanisms underlying exogenous cannabinoid-induced spatial working memory impairment. We found that acute exposure of exogenous cannabinoids induced the impairment of spatial working memory and in vivo long-term depression of synaptic strength at hippocampal CA3-CA1synapses. CB1receptor antagonist blocked memory impairment and synaptic depression induced by exogenous cannabinoid. Memory impairment and synaptic depression was also fully abolished in conditional mutant mice lacking type-1cannabinoid receptors (CB1R) in brain astroglial cells but is conserved in mice lacking CB1R in glutamatergic or GABAergic neurons. The blockade of either neuronal glutamate NMDA receptors or synaptic trafficking of glutamate AMPAR also abolished cannabinoid effects on spatial working memory and LTD induction and expression. Thus, the data indicate that cannabinoid exposure in vivo activates astroglial CB1receptor to increase ambient glutamate, which in turn activates NR2B-containing NMDAR to trigger AMPA receptor internalization at CA3-CA1synapses. These events ultimately induce CB1R-LTD at these synapses, altering the function of hippocampal circuits that likely become unable to process spatial working memory.Altogether, we found that both emotion and memory are implicated in hippocampal synaptic plasticity. Therefore, we speculate that:1. The process of emotion impacting on behavior just share that of memory, because the fundamental basis of behavioral alteration is memory.2. Emotion and memory only share the common mechanism of synaptic plasticity. Learned despair-induced LTP leads to major depression via enhancement of depression related memory. Future studies aimed at determining the changes in molecular signaling that underlies the synaptic potentiation may lead to novel and effective treatments able to reverse some forms of depressive disorders. Therefore, ketamine and cannabinoid lead to antidepressant treatment possibly through impairing depression related memory.