Manipulation of hippocampal CA3 firing via luminopsins modulates spatial and episodic short-term memory, especially working memory, but not long-term memory

The CA3 subregion of the hippocampus is important for rapid encoding, storage and retrieval of associative memories. Lesions and pharmacological inhibitions of hippocampal CA3 suggest that it is essential for different memories. However, how CA3 functions in spatial and episodic memory in different time scales (i.e. short-term versus long term) without permanent lesions has not been systematically investigated yet. Taking advantage of the chemogenetic access to opsins, this study used luminopsins, fusion proteins of luciferase and optogenetic elements, to manipulate neuronal activity in CA3 during memory tasks over a range of spatial and temporal scales. In this study, we found that excitation or inhibition of CA3 neurons had no significant effects on long-term spatial or episodic memory, but had remarkable effects on spatial working memory, spatial short-term memory as well as episodic short-term memory. In addition, stimulation of CA3 neurons altered the expression levels of NR2A. Intracerebral injection of receptor inhibitors further confirmed that NR2A is crucial to spatial working memory, which is consistent with the luminopsins experiments. These findings indicate that CA3 maintains a specific role on spatial and episodic memory over a short period of time.