Activity-dependent neuronal plasticity is a fundamental mechanism through which the nervous system adapts to sensory experience. Several lines of evidence suggest that parvalbumin (PV+) interneurons are essential in this process, but the molecular mechanisms underlying the influence of experience on interneuron plasticity remain poorly understood. Perineuronal nets (PNNs) enwrapping PV+ cells are long-standing candidates for playing such a role, yet their precise contribution has remained elusive. We show that the PNN protein Brevican is a critical regulator of interneuron plasticity. We find that Brevican simultaneously controls cellular and synaptic forms of plasticity in PV+ cells by regulating the localization of potassium channels and AMPA receptors, respectively. By modulating Brevican levels, experience introduces precise molecular and cellular modifications in PV+ cells that are required for learning and memory. These findings uncover a molecular program through which a PNN protein facilitates appropriate behavioral responses to experience by dynamically gating PV+ interneuron function.

How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear. In this study, we investigated transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits in mouse. We found that whether interneurons form synapses on the dendrites, soma, or axon initial segment of pyramidal cells is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus, cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.

SummaryGABAergic activity is thought to influence developing neocortical sensory circuits. Yet the late postnatal maturation of local layer (L)4 circuits suggests alternate sources of GABAergic control in nascent thalamocortical networks. We show that a population of L5b, somatostatin (SST)-positive interneuron receives early thalamic synaptic input and, using laser-scanning photostimulation, identify an early transient circuit between these cells and L4 spiny stellates (SSNs) that disappears by the end of the L4 critical period. Sensory perturbation disrupts the transition to a local GABAergic circuit, suggesting a link between translaminar and local control of SSNs. Conditional silencing of SST+ interneurons or conversely biasing the circuit toward local inhibition by overexpression of neuregulin-1 type 1 results in an absence of early L5b GABAergic input in mutants and delayed thalamic innervation of SSNs. These data identify a role for L5b SST+ interneurons in the control of SSNs in the early postnatal neocortex.

GABAergic interneurons play key roles in cortical circuits, yet little is known about their early connectivity. Here we use glutamate uncaging and a novel optogenetic strategy to track changes in the afferent and efferent synaptic connections of developing neocortical interneuron subtypes. We find that Nkx2-1-derived interneurons possess functional synaptic connections before emerging pyramidal cell networks. Subsequent interneuron circuit maturation is both subtype and layer dependent. Glutamatergic input onto fast spiking (FS), but not somatostatin-positive, non-FS interneurons increases over development. Interneurons of both subtype located in layers (L) 4 and 5b engage in transient circuits that disappear after the somatosensory critical period. These include a pathway mediated by L5b somatostatin-positive interneurons that specifically targets L4 during the first postnatal week. The innervation patterns of immature cortical interneuron circuits are thus neither static nor progressively strengthened but follow a layer-specific choreography of transient connections that differ from those of the adult brain.

The function of cortical GABAergic interneurons is largely determined by their integration into specific neural circuits, but the mechanisms controlling the wiring of these cells remain largely unknown. This is particularly true for a major population of basket cells that express the neuropeptide cholecystokinin (CCK). Here we found that the tyrosine kinase receptor ErbB4 is required for the normal integration of CCK+/VGlut3+ basket cells into cortical circuits. The number of inhibitory synapses made by CCK+/VGlut3+ basket cells and the inhibitory drive they exert on pyramidal cells are severely reduced in conditional mice lacking ErbB4. Developmental disruption of the connectivity of these cells diminishes the power of theta oscillations during exploratory behavior, disrupts spatial coding by place cells, and causes selective alterations in spatial learning and memory in adult mice. These results suggest that normal integration of CCK+ basket cells in cortical networks is key to support spatial coding information in hippocampus.