Transgenic Inhibition of Synaptic Transmission Reveals Role of CA3 Output in Hippocampal Learning

Abstract

The hippocampus is an area of the brain involved in learning and memory. It contains parallel excitatory pathways referred to as the trisynaptic pathway (which carries information as follows: entorhinal cortex --> dentate gyrus --> CA3 --> CA1 --> entorhinal cortex) and the monosynaptic pathway (entorhinal cortex --> CA1 --> entorhinal cortex). We developed a generally applicable tetanus toxin-based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the trisynaptic pathway while preserving transmission in the monosynaptic pathway. We found that synaptic output from CA3 in the trisynaptic pathway is dispensable and the short monosynaptic pathway is sufficient for incremental spatial learning. In contrast, the full trisynaptic pathway containing CA3 is required for rapid one-trial contextual learning, for pattern completion-based memory recall, and for spatial tuning of CA1 cells.

FoxO6 regulates memory consolidation and synaptic function

“…1D). These findings indicate that FoxO6 protein is predominantly expressed in neurons of the CA1 and CA3 regions of the hippocampus-two regions that are important for learning and memory in adult mice (Nakashiba et al 2008;Hunsaker et al 2009;Burgess and O'Keefe 2011).…”

“…Contextual memory formation is known to require the trisynaptic pathway of the hippocampus (involving the CA3, the CA1, and the entorhinal cortex), whereas spatial memory formation requires the monosynaptic pathway (involving the CA1 field and entorhinal cortex) (Nakashiba et al 2008;Hunsaker et al 2009;Burgess and O'Keefe 2011). Thus, FoxO6 may play a more prominent role in the trisynaptic pathway than in the monosynaptic pathway.…”

Updating hippocampal representations: CA2 joins the circuit

“…Similarly, mice with inducible and reversible silencing of CA3-CA1 transmission were able to perform normally in a reference memory version of the Morris water maze [78]. This again suggests that this type of learning can be achieved in the absence of any DG-CA3 contribution to CA1 excitation, although further experiments are necessary to address whether this remaining spatial learning requires CA2 activity.…”

“…This again suggests that this type of learning can be achieved in the absence of any DG-CA3 contribution to CA1 excitation, although further experiments are necessary to address whether this remaining spatial learning requires CA2 activity. At the physiological level, place field recordings from the CA1 region of these mice identified a strong phenotype in the absence of CA3-CA1 transmission [78]: in a novel environment CA1 place fields were present, however the spatial specificity of individual cells was significantly poorer than control neurons and firing rates were elevated, which may again reflect CA2-CA1 rapid-but-inaccurate routes. It has also been reported that there is a slowing of the frequency of the theta rhythm in CA1 in novel environments [79].…”

Selective Manipulation of Neural Circuits

“…The circuit is inactivated through blocking neurotransmission. This system has been used successfully to inactivate neurons and circuits selectively and reversibly [41,42,163,164]. For instance, in order to test the roles of the circuit between propriospinal neurons and spinal motor neurons in dexterous hand movement of primates, AAV encoding reverse tetracycline transactivator was injected into the origin of the circuit where the propriospinal neurons are located, and retrograde gene transfer lentivirus carrying TeNT under the control of tetracycline responsive element was injected into the termination of the circuit where the spinal motor neurons reside.…”