Reconstruction and Simulation of Neocortical Microcircuitry.

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm(3) containing ~31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ~8 million connections with ~37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies. PAPERCLIP: VIDEO ABSTRACT.

Matched pre- and post-synaptic changes underlie synaptic plasticity over long time scales.

Modifications of synaptic efficacies are considered essential for learning and memory. However, it is not known how the underlying functional components of synaptic transmission change over long time scales. To address this question, we studied cortical synapses from young Wistar rats before and after 12 h intervals of spontaneous or glutamate-induced spiking activity. We found that, under these conditions, synaptic efficacies can increase or decrease by up to 10-fold. Statistical analyses reveal that these changes reflect modifications in the number of presynaptic release sites, together with postsynaptic changes that maintain the quantal size per release site. The quantitative relation between the presynaptic and postsynaptic transmission components was not affected when synaptic plasticity was enhanced or reduced using a broad range of pharmacological agents. These findings suggest that ongoing synaptic plasticity results in matched presynaptic and postsynaptic modifications, in which elementary modules that span the synaptic cleft are added or removed as a function of experience.

Enhanced long-term microcircuit plasticity in the valproic Acid animal model of autism.

A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a minicolumn (<50 µm). In the present study, we explored whether Long Term Microcircuit Plasticity (LTMP) was altered in this animal model. We performed multi-neuron patch-clamp recordings on clusters of layer 5 pyramidal cells in somatosensory cortex brain slices (PN 12-15), mapped the connectivity and characterized the synaptic properties for connected neurons. Pipettes were then withdrawn and the slice was perfused with 100 µM sodium glutamate in artificial cerebrospinal fluid in the recording chamber for 12 h. When we re-patched the same cluster of neurons, we found enhanced LTMP only at inter-somatic distances beyond minicolumnar dimensions. These data suggest that hyperconnectivity is already near its peak within the dimensions of the minicolumn in the treated animals and that LTMP, which is normally restricted to within a minicolumn, spills over to drive hyperconnectivity across the dimensions of a minicolumn. This study provides further evidence to support the notion that the neocortex is highly plastic in response to new experiences in this animal model of autism.

Morphological, electrophysiological, and synaptic properties of corticocallosal pyramidal cells in the neonatal rat neocortex.

Neocortical pyramidal cells (PCs) project to various cortical and subcortical targets. In layer V, the population of thick tufted PCs (TTCs) projects to subcortical targets such as the tectum, brainstem, and spinal cord. Another population of layer V PCs projects via the corpus callosum to the contralateral neocortical hemisphere mediating information transfer between the hemispheres. This subpopulation (corticocallosally projecting cells [CCPs]) has been previously described in terms of their morphological properties, but less is known about their electrophysiological properties, and their synaptic connectivity is unknown. We studied the morphological, electrophysiological, and synaptic properties of CCPs by retrograde labeling with fluorescent microbeads in P13-P16 Wistar rats. CCPs were characterized by shorter, untufted apical dendrites, which reached only up to layers II/III, confirming previous reports. Synaptic connections between CCPs were different from those observed between TTCs, both in probability of occurrence and dynamic properties. We found that the CCP network is about 4 times less interconnected than the TTC network and the probability of release is 24% smaller, resulting in a more linear synaptic transmission. The study shows that layer V pyramidal neurons projecting to different targets form subnetworks with specialized connectivity profiles, in addition to the specialized morphological and electrophysiological intrinsic properties.

Spontaneous and evoked synaptic rewiring in the neonatal neocortex.

The local microcircuitry of the neocortex is structurally a tabula rasa, with the axon of each pyramidal neuron having numerous submicrometer appositions with the dendrites of all neighboring pyramidal neurons, but is functionally highly selective, with synapses formed onto only a small proportion of these targets. This design leaves a vast potential for the microcircuit to rewire without extensive axonal or dendritic growth. To examine whether rewiring does take place, we used multineuron patch-clamp recordings on 12- to 14-day-old rat neocortical slices and studied long-term changes in synaptic connectivity within clusters of neurons. We found pyramidal neurons spontaneously connecting and disconnecting from each other and that exciting the slice with glutamate greatly increases the number of new connections established. Evoked emergence of new synaptic connections requires action potential activity and activation of metabotropic glutamate receptor 5, but not NMDA receptor or group II or group III metabotropic glutamate receptor activation. We also found that it is the weaker connections that are selectively eliminated. These results provide direct evidence for spontaneous and evoked rewiring of the neocortical microcircuitry involving entire functional multisynaptic connections. We speculate that this form of microcircuit plasticity enables an evolution of the microcircuit connectivity by natural selection as a function of experience.