Development of differential sublaminar feedforward inhibitory circuits in CA1 hippocampus requires Satb2.

Abstract

Pyramidal cells (PCs) in CA1 hippocampus can be classified by their radial position as deep or superficial and organize into subtype-specific circuits necessary for differential information processing. Specifically, superficial PCs receive fewer inhibitory synapses from parvalbumin (PV)-expressing interneurons than deep PCs, resulting in weaker feedforward inhibition of input from CA3 Schaffer collaterals. Using mice, we investigated mechanisms underlying CA1 PC differentiation and the development of this inhibitory circuit motif. We found that the transcriptional regulator SATB2, which is necessary for pyramidal cell differentiation in the neocortex, is selectively expressed in superficial PCs during early postnatal development. To investigate its role in CA1, we conditionally knocked out Satb2 from pyramidal cells during embryonic development using both male and female Emx1^IRES-Cre;Satb2^flox/flox mice. Loss of Satb2 resulted in increased feedforward inhibition of CA3 Schaffer collateral input to superficial PCs, which matched that observed to deep PCs in control mice. Using paired whole-cell recordings between PCs and PV+ interneurons, we found this was due to an increase in the strength of unitary inhibitory synaptic connections from PV+ interneurons to mutant superficial PCs. Regulation of synapse strength was restricted to inhibitory synapses; excitatory synaptic connections from CA3 to CA1 PCs and from CA1 PCs to PV+ interneurons were not affected by loss of Satb2 Finally, we show that SATB2 expression in superficial PCs is necessary to suppress the formation of synapses from PV+ interneurons during synaptogenesis. Thus, early postnatal expression of SATB2 in superficial PCs is necessary for the development of biased feedforward inhibition in CA1.Significance statement Deep and superficial pyramidal cells (PCs) in CA1 hippocampus are distinct subtypes that integrate into separate circuits to provide unique hippocampal computations to the rest of the brain. The mechanisms that determine the identity and circuit integration of each PC subtype are unclear. Here, we show that expression of the transcriptional regulator Satb2 in superficial PCs is necessary to suppress the formation of inhibitory synapses from PV+ interneurons during early development. This is critical to reduce feedforward inhibition of CA3 Schaffer collateral input to superficial PCs relative to deep PCs in mature circuits. Our data provide insight into the development of cell-type-specific circuits in the hippocampus, which is crucial for determining how they function to support learning and memory.