Hippocampal CA3 inhibitory neurons receive extensive noncanonical synaptic inputs from CA1 and subicular complex

Hippocampal CA3 is traditionally conceptualized as a brain region within a unidirectional feedforward trisynaptic pathway that links major hippocampal subregions. Recent genomic and viral tracing studies indicate that the anatomical connectivity of CA3 and the trisynaptic pathway is more complex than initially expected and suggests that there may be cell type-specific input gradients throughout the three-dimensional hippocampal structure. In several recent studies using multiple viral tracing approaches, we describe subdivisions of the subiculum complex and ventral hippocampal CA1 that show significant back projections to CA1 and CA3 excitatory neurons. These novel connections form noncanonical circuits that run in the opposite direction relative to the well-characterized feedforward pathway. Diverse subtypes of GABAergic inhibitory neurons participate within the trisynaptic pathway. In the present study, we have applied monosynaptic retrograde viral tracing to examine noncanonical synaptic inputs from CA1 and subicular complex to the inhibitory neuron in hippocampal CA3. We quantitatively mapped synaptic inputs to CA3 inhibitory neurons to understand how they are connected within and beyond the hippocampus formation. Major brain regions that provide typical inputs to CA3 inhibitory neurons include the medial septum, the dentate gyrus, the entorhinal cortex, and CA3. Noncanonical inputs from ventral CA1 and subicular complex to CA3 inhibitory neurons follow a proximodistal topographic gradient with regard to CA3 subregions. We find novel noncanonical circuit connections between inhibitory CA3 neurons and ventral CA1, subiculum complex, and other brain regions. These results provide a new anatomical connectivity basis to further study the function of CA3 inhibitory neurons.

Automated summary

Traditionally, hippocampal CA3 is thought to be part of a unidirectional feedforward trisynaptic pathway. However, recent studies using genomic and viral tracing techniques have revealed that the anatomical connectivity of CA3 and the trisynaptic pathway is more complex than expected, with cell type-specific input gradients throughout the hippocampal structure. These studies also identified noncanonical circuit connections between CA3 inhibitory neurons and ventral CA1, subiculum complex, and other brain regions, suggesting a more intricate network than previously thought. Understanding these novel connections provides a basis for further investigating the function of CA3 inhibitory neurons.