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

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 PC differentiation and the development of this inhibitory circuit motif. We found that expression of the transcriptional regulator SATB2 is biased towards superficial PCs during early postnatal development and necessary to suppress PV+ interneuron synapse formation. In the absence of SATB2, the number of PV+ interneuron synaptic puncta surrounding superficial PCs increases during development to match deep PCs. This results in equivalent inhibitory current strength observed in paired whole-cell recordings, and equivalent feedforward inhibition of Schaffer collateral input. Thus, SATB2 is necessary for superficial PC differentiation and biased feedforward inhibition in CA1.

Arid1b haploinsufficiency in cortical inhibitory interneurons causes cell-type-dependent changes in cellular and synaptic development.

Autism spectrum disorder (ASD) presents with diverse cognitive and behavioral abnormalities beginning during early development. Although the neural circuit mechanisms remain unclear, recent work suggests pathology in cortical inhibitory interneurons (INs) plays a crucial role. However, we lack fundamental information regarding changes in the physiology of synapses to and from INs in ASD. Here, we used transgenic mice to conditionally knockout one copy of the high confidence ASD risk gene Arid1b from the progenitors of parvalbumin-expressing fast-spiking (PV-FS) INs and somatostatin-expressing non-fast-spiking (SST-NFS) INs. In brain slices, we performed paired whole-cell recordings between INs and excitatory projection neurons (PNs) to investigate changes in synaptic physiology. In neonates, we found reduced synaptic input to INs but not PNs, with a concomitant reduction in the frequency of spontaneous network events, which are driven by INs in immature circuits. In mature mice, we found a reduction in the number of PV-FS INs in cortical layers 2/3 and 5. However, changes in PV-FS IN synaptic physiology were cortical layer and PN cell-type dependent. In layer 5, synapses from PV-FS INs to subcortical-projecting PNs were weakened. In contrast, in layer 2/3, synapses to and from PV-FS INs and corticocortical-projecting PNs were strengthened, leading to enhanced feedforward inhibition of input from layer 4. Finally, we found a novel synaptic deficit among SST-NFS INs, in which excitatory synapses from layer 2/3 PNs failed to facilitate. Our data highlight that changes in unitary synaptic dynamics among INs in ASD depend on neuronal cell-type.

Arid1b haploinsufficiency in pyramidal neurons causes cellular and circuit changes in neocortex but is not sufficient to produce behavioral or seizure phenotypes.

Arid1b is a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex expressed in neuronal progenitors. Haploinsufficiency causes a broad range of social, behavioral, and intellectual disability phenotypes, including Coffin-Siris syndrome. Recent work using transgenic mouse models suggests pathology is due to deficits in proliferation, survival, and synaptic development of cortical neurons. However, there is conflicting evidence regarding the relative roles of excitatory projection neurons and inhibitory interneurons in generating abnormal cognitive and behavioral phenotypes. Here, we conditionally knocked out either one or both copies of Arid1b from excitatory projection neuron progenitors and systematically investigated the effects on intrinsic membrane properties, synaptic physiology, social behavior, and seizure susceptibility. We found that disrupting Arid1b expression in excitatory neurons alters their membrane properties, including hyperpolarizing action potential threshold; however, these changes depend on neuronal subtype. Using paired whole-cell recordings, we found increased synaptic connectivity rate between projection neurons. Furthermore, we found reduced strength of excitatory synapses to parvalbumin (PV)-expression inhibitory interneurons. These data suggest an increase in the ratio of excitation to inhibition. However, the strength of inhibitory synapses from PV interneurons to excitatory neurons was enhanced, which may rebalance this ratio. Indeed, Arid1b haploinsufficiency in projection neurons was insufficient to cause social deficits and seizure phenotypes observed in a preclinical germline haploinsufficient mouse model. Our data suggest that while excitatory projection neurons likely contribute to autistic phenotypes, pathology in these cells is not the primary cause.

Advances in approaches to study cell-type specific cortical circuits throughout development.

Neurons in the neocortex and hippocampus are diverse and form synaptic connections that depend on their type. Recent work has improved our understanding of neuronal cell-types and how to target them for experiments. This is crucial for investigating cortical circuit architecture, as the current catalog of established cell-type specific circuit motifs is small relative to the diversity of neuronal subtypes. Some of these motifs are found throughout the cortex, suggesting they are canonical circuits necessary for basic computations. However, the extent to which circuit organization is stereotyped across the brain or varies by cortical region remains unclear. Cortical circuits are also plastic, and their organization evolves throughout each developmental stage. Thus, experimental access to neuronal subtypes with temporal control is essential for studying cortical structure and function. In this mini review, we highlight several recent advances to target specific neuronal subtypes and study their synaptic connectivity and physiology throughout development. We emphasize approaches that combine multiple techniques, provide examples of successful applications, and describe potential future applications of novel tools.