We present a unique, extensive, and open synaptic physiology analysis platform and dataset. Through its application, we reveal principles that relate cell type to synaptic properties and intralaminar circuit organization in the mouse and human cortex. The dynamics of excitatory synapses align with the postsynaptic cell subclass, whereas inhibitory synapse dynamics partly align with presynaptic cell subclass but with considerable overlap. Synaptic properties are heterogeneous in most subclass-to-subclass connections. The two main axes of heterogeneity are strength and variability. Cell subclasses divide along the variability axis, whereas the strength axis accounts for substantial heterogeneity within the subclass. In the human cortex, excitatory-to-excitatory synaptic dynamics are distinct from those in the mouse cortex and vary with depth across layers 2 and 3.

Generating a comprehensive description of cortical networks requires a large-scale, systematic approach. To that end, we have begun a pipeline project using multipatch electrophysiology, supplemented with two-photon optogenetics, to characterize connectivity and synaptic signaling between classes of neurons in adult mouse primary visual cortex (V1) and human cortex. We focus on producing results detailed enough for the generation of computational models and enabling comparison with future studies. Here, we report our examination of intralaminar connectivity within each of several classes of excitatory neurons. We find that connections are sparse but present among all excitatory cell classes and layers we sampled, and that most mouse synapses exhibited short-term depression with similar dynamics. Synaptic signaling between a subset of layer 2/3 neurons, however, exhibited facilitation. These results contribute to a body of evidence describing recurrent excitatory connectivity as a conserved feature of cortical microcircuits.

Key points• In mouse models for retinal degeneration, photoreceptor death leads to membrane oscillation in the remnant AII amacrine-ON cone bipolar cell network through an unknown mechanism.• We found such oscillations require voltage-gated Na + channels and gap junctions but not hyperpolarization-activated currents (I h ).• Na + channels are expressed predominantly in AII amacrine cells and I h in ON cone bipolar cells, and appear to interact via gap junctions to shape oscillations.• Similar intrinsic oscillations arose in the wild-type (wt) AII amacrine-ON cone bipolar cell network when photoreceptor inputs to bipolar cells were pharmacologically occluded.• Computational modelling captures experimental findings when a low level of cellular heterogeneity is introduced in the coupled network.• These unique insights into the cellular mechanisms underlying spontaneous activity in the degenerating retina might aid in designing the most effective strategies to restore vision using retinal prosthesis. AbstractIn the rd1 mouse model for retinal degeneration, the loss of photoreceptors results in oscillatory activity (∼10-20 Hz) within the remnant electrically coupled network of retinal ON cone bipolar and AII amacrine cells. We tested the role of hyperpolarization-activated currents (I h ), voltage-gated Na + channels and gap junctions in mediating such oscillatory activity. Blocking I h (1 mM Cs + ) hyperpolarized the network and augmented activity, while antagonizing voltage-dependent Na + channels (1 μM TTX) abolished oscillatory activity in the AII amacrine-ON cone bipolar cell network. Voltage-gated Na + channels were only observed in AII amacrine cells, implicating these cells as major drivers of activity. Pharmacologically uncoupling the network (200 μM meclofenamic acid (MFA)) blocked oscillations in all cells indicating that Na + channels exert their influence over multiple cell types within the network. In wt retina, occluding photoreceptor inputs to bipolar cells (10 μM NBQX and 50 μM L-AP4) resulted in a mild (∼10 mV) hyperpolarization and the induction of oscillatory activity within the AII amacrine-ON cone bipolar cell network. These oscillations had similar properties to those observed in rd1 retina, suggesting that no major degeneration-induced network rewiring is required to trigger spontaneous oscillations. Finally, we constructed a simplified computational model that exhibited Na + channel-dependent network oscillations. In this model, mild heterogeneities in channel densities between individual neurons reproduced our experimental findings. These results indicate that TTX-sensitive Na + channels in AII amacrine cells trigger degeneration-induced network oscillations, which provide a persistent synaptic drive to downstream remnant neurons, thus appearing to replace photoreceptors as the principal drivers of retinal activity.