Role of subunit composition of hippocampal N-Methyl-D-Aspartate (NMDA) receptors in the extinction of contextual fear
Final Report Abstract
Emotional states of individuals are modulated by social factors, e.g. positive social interactions can be anxiolytic whereas negative or stressful interactions can increase symptoms of anxiety. Hence, people with a supportive social environment are better in health than the ones with fewer supportive social contacts. Also, it has been shown that social support is beneficial for patients with posttraumatic stress disorder or depression. Lack of support or social stress, however, can exacerbate or even induce neurological disorders linked to anxiety or depression. Besides that, also an impaired perception and processing of social stimuli is linked to neurological disorders. For example, the autism spectrum disorder is a syndrome that is characterized by impaired social interactions but also repetitive and stereotypic behavior. On the neuroanatomic level, the hippocampus and the lateral septum have been largely involved in processing of social stimuli and fear responses. The hippocampus is a necessity for acquisition of fear conditioning to a context in mice and is also involved in social learning. The lateral septum is largely connected to the amygdala and is a part of the fear-learning circle. This region has also been identified as a key region for modulation of contextual fear conditioning by chronic social stress in mice. One of the main receptor classes involved in fear acquisition but also social learning are glutamate receptors. Blocking NMDA receptors in the hippocampus can prevent fear acquisition but also impair social learning. Besides that, oxytocin receptors have been shown to be involved in processing of fear response since administration of oxytocin ameliorates fear. Furthermore, it was shown that blocking oxytocin receptors in the lateral septum blocks the modulation of social stress on fear conditioning in mice. Therefore, in this study I analyzed the role of glutamatergic and oxytocinergic receptors in the hippocampus and the lateral septum in social behavior. It seems that NR3-NMDA receptors in the hippocampus might be involved in formation of social memory in mice since we observed impairment after employment of NR3BshRNA. General memory formation, as indicated by intact contextual freezing response, and depression-like behavior seem to be unaffected. But this has to be proven in further studies. mGluR5 receptors in the hippocampus were shown to be important for the sociability in mice, as indicated by impairment of social preference after genetic knockdown. These receptors could be a potential target for therapies of the autism spectrum disorder. However, the mGluR5 knockdown in the lateral septum did not have an effect on contextual fear conditioning implying that these receptors are not involved in social modulation of fear response. We found that the oxytocin system is a key mediator of lasting reduction of freezing caused by positive social interactions as this effect was abolished either by genetic Oxtr-knockdown or antagonism. These findings are important since they imply how administration of oxytocin can facilitate reduction of fear after positive social interactions and they can be of potential use in order to develop therapies for patients with anxiety-disorders.
