The rapid developmental rise of somatic inhibition disengages hippocampal dynamics from self-motion

Early electrophysiological brain oscillations recorded in preterm babies and newborn rodents are initially mostly ignited by bottom-up sensorimotor activity and only later can detach from external inputs. This is a hallmark of most developing brain areas including the hippocampus, which in the adult brain, functions in integrating external inputs onto internal dynamics. Such developmental disengagement from external inputs is likely a fundamental step for the proper development of cognitive internal models. Despite its importance, the exact timing and circuit basis for this disengagement remain unknown. To address this issue, we have investigated the daily evolution of CA1 dynamics and underlying circuits during the first and second postnatal week of mouse development using a combination of two-photon calcium imaging of neuronal somata and axons in non-anesthetized pups, viral tracing and chemogenetics. We show that the first postnatal week ends with an abrupt switch in the representation of self-motion in CA1. Indeed, most CA1 pyramidal cells switch from activated to inhibited by self-generated movements at the end of the first postnatal week whereas GABAergic neurons remain positively modulated throughout this period. This rapid switch occurs within two days and is mediated by the rapid anatomical and functional surge of somatic inhibition. The observed dynamics is consistent with a two-population model undergoing strengthening inhibition. Remarkably, a transient silencing of local somatostatin-expressing interneurons both prevents the emergence of the perisomatic GABAergic coverage and the disengagement of CA1 hippocampal dynamics from self-motion. We propose that such activity-dependent emergence of feedback inhibitory circuits critically inaugurates the development of internal cognitive models.

Experience-dependent inhibitory plasticity is mediated by CCK+ basket cells in the developing dentate gyrus

Early postnatal experience shapes both inhibitory and excitatory networks in the hippocampus. However, the underlying circuit plasticity is unclear. Using an enriched environment (EE) paradigm, we assessed the circuit plasticity of inhibitory cell-types in the hippocampus. We found that cholecystokinin (CCK)-expressing basket cells strongly increased somatic inhibition on the excitatory granular cells (GC) following EE while another pivotal inhibitory cell-type, parvalbumin (PV)-expressing cells did not show changes. By inhibiting activity of the entorhinal cortex (EC) using a chemogenetic approach, we demonstrate that the projections from the EC is responsible for the developmental plasticity of CCK+ basket cells. Our measurement of the input decorrelation by DG circuit suggests that EE has little effect on pattern separation despite of the altered CCK+ basket cell circuit. Altogether, our study places the activity-dependent remodeling of CCK+ basket cell innervation as a central process to adjust inhibition in the DG, while maintaining the computation in the circuit.

Robust perisomatic GABAergic self-innervation inhibits basket cells in the human and mouse supragranular neocortex

Inhibitory autapses are self-innervating synaptic connections in GABAergic interneurons in the brain. Autapses in neocortical layers have not been systematically investigated, and their function in different mammalian species and specific interneuron types is poorly known. We investigated GABAergic parvalbumin-expressing basket cells (pvBCs) in layer 2/3 (L2/3) in human neocortical tissue resected in deep-brain surgery, and in mice as control. Most pvBCs showed robust GABAAR-mediated self-innervation in both species, but autapses were rare in nonfast-spiking GABAergic interneurons. Light- and electron microscopy analyses revealed pvBC axons innervating their own soma and proximal dendrites. GABAergic self-inhibition conductance was similar in human and mouse pvBCs and comparable to that of synapses from pvBCs to other L2/3 neurons. Autaptic conductance prolonged somatic inhibition in pvBCs after a spike and inhibited repetitive firing. Perisomatic autaptic inhibition is common in both human and mouse pvBCs of supragranular neocortex, where they efficiently control discharge of the pvBCs.

Robust perisomatic GABAergic self-innervation inhibits basket cells in the human and mouse supragranular neocortex

ABSTRACTInhibitory autapses are self-innervating synaptic connections in GABAergic interneurons in the brain. Autapses in neocortical layers have not been systematically investigated, and their function in different mammalian species and specific interneuron types is poorly known. We investigated GABAergic parvalbumin-expressing basket cells (pvBCs) in layer 2/3 (L2/3) in mice as well as in human neocortical tissue resected in deep-brain surgery. Most pvBCs showed robust GABAAR-mediated self-innervation in both species, but autapses were rare in nonfast spiking GABAergic interneurons. Light- and electron microscopy analyses revealed pvBC axons innervating their own soma and proximal dendrites. GABAergic self-inhibition conductance was similar in human and mouse pvBCs and comparable to that of synapses from pvBCs to other L2/3 neurons. Autaptic conductance prolonged somatic inhibition in pvBCs after a spike and inhibited repetitive firing. Perisomatic autaptic inhibition has evolved in pvBCs of various cortical layers and different mammalian species to control discharge of these interneurons.

Sparse Coding with a Somato-Dendritic Rule

Cortical neurons are silent most of the time. This sparse activity is energy efficient, and the resulting neural code has favourable properties for associative learning. Most neural models of sparse coding use some form of homeostasis to ensure that each neuron fires infrequently. But homeostatic plasticity acting on a fast timescale may not be biologically plausible, and could lead to catastrophic forgetting in embodied agents that learn continuously. We set out to explore whether inhibitory plasticity could play that role instead, regulating both the population sparseness and the average firing rates. We put the idea to the test in a hybrid network where rate-based dendritic compartments integrate the feedforward input, while spiking somas compete through recurrent inhibition. A somato-dendritic learning rule allows somatic inhibition to modulate nonlinear Hebbian learning in the dendrites. Trained on MNIST digits and natural images, the network discovers independent components that form a sparse encoding of the input and support linear decoding. These findings con-firm that intrinsic plasticity is not strictly required for regulating sparseness: inhibitory plasticity can have the same effect, although that mechanism comes with its own stability-plasticity dilemma. Going beyond point neuron models, the network illustrates how a learning rule can make use of dendrites and compartmentalised inputs; it also suggests a functional interpretation for clustered somatic inhibition in cortical neurons.

NPAS4 recruits CCK basket cell synapses and enhances cannabinoid-sensitive inhibition in the mouse hippocampus

Experience-dependent expression of immediate-early gene transcription factors (IEG-TFs) can transiently change the transcriptome of active neurons and initiate persistent changes in cellular function. However, the impact of IEG-TFs on circuit connectivity and function is poorly understood. We investigate the specificity with which the IEG-TF NPAS4 governs experience-dependent changes in inhibitory synaptic input onto CA1 pyramidal neurons (PNs). We show that novel sensory experience selectively enhances somatic inhibition mediated by cholecystokinin-expressing basket cells (CCKBCs) in an NPAS4-dependent manner. NPAS4 specifically increases the number of synapses made onto PNs by individual CCKBCs without altering synaptic properties. Additionally, we find that sensory experience-driven NPAS4 expression enhances depolarization-induced suppression of inhibition (DSI), a short-term form of cannabinoid-mediated plasticity expressed at CCKBC synapses. Our results indicate that CCKBC inputs are a major target of the NPAS4-dependent transcriptional program in PNs and that NPAS4 is an important regulator of plasticity mediated by endogenous cannabinoids.