Developmental mechanisms underlying the generation of cortical interneuron diversity

GABAergic interneurons are critical components of cortical circuits. However, understanding their function has become extremely challenging because they constitute one of the most diverse groups of cells in the central nervous system. Indeed, cortical GABAergic interneurons are heterogeneous in so many different ways--morphology, molecular profiling, electrical properties--that even attempts to discern what parameters should be used to identify cortical interneuron subtypes have failed to generate broad consensus among experts in the field. The extent to which cortical interneuron diversity emerges during development is largely unknown, but it is likely that insights on how this process takes place may help us understand their role as integrative and synchronizing elements in cortical function. Here, we review recent data on how the large variety of distinct classes of cortical interneurons may arise during development.     

Precocious pathfinding: retinal axons can navigate in an axonless brain.

The developing axons of retinal ganglion cells follow a stereotyped trajectory through the diencephalon to the optic tectum. In Xenopus, this trajectory closely parallels that of a preexisting fiber tract, the tract of the postoptic commissure (TPOC). This tract comprises part of the early CNS scaffold and has been proposed to play a critical role in guiding the later growing optic axons. We have tested this possibility using heterochronic and xenoplastic transplants of eye primordia to force optic axons to enter the brain before scaffold tracts have arisen in the forebrain. We show that optic axons can navigate appropriately in the absence of the TPOC or any other axons, indicating that axonal pathfinding cues are present in the axonless neuroepithelial sheet. We suggest that molecularly distinct heterogeneities within the neuroepithelium are used for pathfinding by early and late developing axons alike in normal development.     

The spike generation zone of the ampullary electroreceptor

Sensory input to the central nervous system begins with a transduction step, specialized to the sensory modality involved, resulting in the production of postsynaptic electrical input to the outermost branches of a dendritic tree. Spatiotemporal summation of this slow input as it converges upon the axon then initiates the production of or modulates the rate of ongoing production of fast neural spikes destined for the central nervous system. We present a novel circuit design consisting of an operational amplifier, a tunnel diode and linear passive components, intended to model the spike generation zone at which the transformation of neural input from slow to fast format takes place. Our circuit is shown to be a relaxation oscillator of the van der Pol type. Simulated postsynaptic current modulates the frequency of spike production by the relaxation oscillator model, producing a stimulus-response characteristic which can be compared with those observed in vivo. Stimulus-response data for our model match data available in the literature for the ampullary electroreceptor of elasmobranch fish.     

Synaptic mechanisms of spike generation in bursts by neurons of the carp tectum and olfactory bulb

Synaptic mechanisms of burst activity generation in certain neurons of the tectum opticum and mechanisms of generation of stimulation-induced group discharges by certain secondary neurons of the olfactory bulb were analyzed in carp (Cyprinus carpio L.). Spikes of the spontaneous discharge in neurons of the tectum were accompanied by depolarizing after-potentials, which caused the burst discharges of these cells. Evidence is given in support of the synaptic nature of the after-potential; it is suggested that it is generated by a recurrent collateral mechanism. Synaptic bombardment causing the appearance of a group discharge in olfactory bulb neurons and groups of spikes in their spontaneous activity was found to be intermittent in character. These features of unit activity in the olfactory bulb are shown to be connected with the presence of excitatory synaptic interaction between several neurons, probably dendro-dendritic in nature.M. V. Lomonosov Moscow State University. Translated from Neirofiziologiay, Vol. 14, No. 5, pp. 483–490, September–October, 1982.     

Postsynaptic mechanisms initiating bursting activity in theHelix pomatia RPal neuron under the influence of an interneuron

Postsynaptic mechanisms of the connection between the interneuron in the visceral ganglion initiating bursting activity in RPal and B7 neurons and these neurons themselves were investigated in the snail (Helix pomatia). Using voltage clamping at the membrane of these cells, stimulation of the interneuron gave rise to a slow inward current with a 2 sec latency; it rose in amplitude as stimulation increased in duration. Reducing the temperature from 25 to 5°C diminished the rise and decay rate of this current with a temperature coefficient of about 10. The current-voltage relationship of the slow inward current was nonlinear, with a maximum of –65 mV. Reducing the concentration of sodium ions in the extracellular fluid increased the amplitude of the current. While hyperpolarization of the burster neuron membrane produced a burst of inward current prior to stimulation, this same hyperpolarization induced a pulse of outward current at the peak of the slow inward current. Stimulating the interneuron is thus thought to activate at least two types of ionic channel in the cell body of the burster neurons: a steady sodium and a voltage- and time-dependent channel for outward current. This process could well be mediated by a biochemical cytoplasmic chain reaction.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 19, No. 1, pp. 28–36, January–February, 1987.     

Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks

Gamma frequency oscillations are thought to provide a temporal structure for information processing in the brain. They contribute to cognitive functions, such as memory formation and sensory processing, and are disturbed in some psychiatric disorders. Fast-spiking, parvalbumin-expressing, soma-inhibiting interneurons have a key role in the generation of these oscillations. Experimental analysis in the hippocampus and the neocortex reveals that synapses among these interneurons are highly specialized. Computational analysis further suggests that synaptic specialization turns interneuron networks into robust gamma frequency oscillators.     

The neuronal mechanisms of respiratory rhythm generation

New, improved in vivo and in vitro approaches have led to a better understanding of the mechanisms that generate respiratory rhythm, which depends on a complex interaction between network and intrinsic membrane properties. The pre-Bötzinger complex in the ventrolateral medulla is particularly important for respiratory rhythm generation. This complex can be studied in isolation, and it contains all the known types of respiratory neurons that are now amenable to detailed cellular and molecular analyses.     

Network variability limits stimulus-evoked spike timing precision in retinal ganglion cells

Visual, auditory, somatosensory, and olfactory stimuli generate temporally precise patterns of action potentials (spikes). It is unclear, however, how the precision of spike generation relates to the pattern and variability of synaptic input elicited by physiological stimuli. We determined how synaptic conductances evoked by light stimuli that activate the rod bipolar pathway control spike generation in three identified types of mouse retinal ganglion cells (RGCs). The relative amplitude, timing, and impact of excitatory and inhibitory input differed dramatically between On and Off RGCs. Spikes evoked by repeated somatic injection of identical light-evoked synaptic conductances were more temporally precise than those evoked by light. However, the precision of spikes evoked by conductances that varied from trial to trial was similar to that of light-evoked spikes. Thus, the rod bipolar pathway modulates different RGCs via unique combinations of synaptic input, and RGC temporal variability reflects variability in the input this circuit provides.     

Spatial and temporal correlations of spike trains in frog retinal ganglion cells

For a neuron, firing activity can be in synchrony with that of others, which results in spatial correlation; on the other hand, spike events within each individual spike train may also correlate with each other, which results in temporal correlation. In order to investigate the relationship between these two phenomena, population neurons’ activities of frog retinal ganglion cells in response to binary pseudo-random checker-board flickering were recorded via a multi-electrode recording system. The spatial correlation index (SCI) and temporal correlation index (TCI) were calculated for the investigated neurons. Statistical results showed that, for a single neuron, the SCI and TCI values were highly related—a neuron with a high SCI value generally had a high TCI value, and these two indices were both associated with burst activities in spike train of the investigated neuron. These results may suggest that spatial and temporal correlations of single neuron’s spiking activities could be mutually modulated; and that burst activities could play a role in the modulation. We also applied models to test the contribution of spatial and temporal correlations for visual information processing. We show that a model considering spatial and temporal correlations could predict spikes more accurately than a model does not include any correlation.     

A cross-interval spike train analysis: the correlation between spike generation and temporal integration of doublets

A stochastic spike train analysis technique is introduced to reveal the correlation between the firing of the next spike and the temporal integration period of two consecutive spikes (i.e., a doublet). Statistics of spike firing times between neurons are established to obtain the conditional probability of spike firing in relation to the integration period. The existence of a temporal integration period is deduced from the time interval between two consecutive spikes fired in a reference neuron as a precondition to the generation of the next spike in a compared neuron. This analysis can show whether the coupled spike firing in the compared neuron is correlated with the last or the second-to-last spike in the reference neuron. Analysis of simulated and experimentally recorded biological spike trains shows that the effects of excitatory and inhibitory temporal integration are extracted by this method without relying on any subthreshold potential recordings. The analysis also shows that, with temporal integration, a neuron driven by random firing patterns can produce fairly regular firing patterns under appropriate conditions. This regularity in firing can be enhanced by temporal integration of spikes in a chain of polysynaptically connected neurons. The bandpass filtering of spike firings by temporal integration is discussed. The results also reveal that signal transmission delays may be attributed not just to conduction and synaptic delays, but also to the delay time needed for temporal integration. Received: 3 March 1997 / Accepted in revised form: 6 November 1997     

Central inhibition of an identified mechanosensory interneuron in the crayfish

Inhibitory input from crayfish mechanoreceptors is mediated polysynaptically to sensory interneurons. An identifiable sensory interneuron, the caudal photoreceptor (CPR), has been used as a model system to characterize inhibitory intermediate cells. A survey of the abdominal connectives, by antidromic stimulation, has identified eleven inhibitory cells, some of which also function as ascending sensory interneurons. These results indicate that lateral interactions within networks of mechanosensory interneurons form an integral part of the information processing mechanisms.     

Calcium-dependent increase in spike duration during repetitive firing of Aplysia axon in the presence of TEA

Repetitive stimulation was studied in the axon of the giant neuron, R2, of Aplysia in the presence of TEA. In 25 or 50 mM extracellular TEA, a plateau develops on the axon spike during repetitive stimulation at frequencies greater than 3/sec. The plateau in extracellular TEA is inhibited by 30 mM CoCl₂ or 1 mM CdCl₂, and is enhanced by raising the Ca concentration. Intracellular TEA induces a plateau on the axon spike at frequencies less than 1/30sec. This plateau increases in duration with repetitive stimulation at higher frequencies and is inhibited by 30 mM CoCl₂ or 1 mM CdCl₂. The increase in spike duration during repetitive firing in the presence of TEA is indicative of an increased entry of Ca during the spike train.     

The binding of heparin to spike glycoprotein inhibits SARS-CoV-2 infection by three mechanisms

Heparin, a naturally occurring glycosaminoglycan, has been found to have antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of COVID-19. To elucidate the mechanistic basis for the antiviral activity of heparin, we investigated the binding of heparin to the SARS-CoV-2 spike glycoprotein by means of sliding window docking, molecular dynamics simulations, and biochemical assays. Our simulations show that heparin binds at long, positively charged patches on the spike glycoprotein, thereby masking basic residues of both the receptor-binding domain (RBD) and the multifunctional S1/S2 site. Biochemical experiments corroborated the simulation results, showing that heparin inhibits the furin-mediated cleavage of spike by binding to the S1/S2 site. Our simulations showed that heparin can act on the hinge region responsible for motion of the RBD between the inactive closed and active open conformations of the spike glycoprotein. In simulations of the closed spike homotrimer, heparin binds the RBD and the N-terminal domain of two adjacent spike subunits and hinders opening. In simulations of open spike conformations, heparin induces stabilization of the hinge region and a change in RBD motion. Our results indicate that heparin can inhibit SARS-CoV-2 infection by three mechanisms: by allosterically hindering binding to the host cell receptor, by directly competing with binding to host heparan sulfate proteoglycan coreceptors, and by preventing spike cleavage by furin. Furthermore, these simulations provide insights into how host heparan sulfate proteoglycans can facilitate viral infection. Our results will aid the rational optimization of heparin derivatives for SARS-CoV-2 antiviral therapy.     

Central inhibition of an identified mechanosensory interneuron in the crayfish.

Inhibitory input from crayfish mechanoreceptors is mediated polysynaptically to sensory interneurons. An identifiable sensory interneuron, the caudal photoreceptor (CPR), has been used as a model system to characterize inhibitory intermediate cells. A survey of the abdominal connectives, by antidromic stimulation, has identified eleven inhibitory cells, some of which also function as ascending sensory interneurons. These results indicate that lateral interactions within networks of mechanosensory interneurons form an integral part of the information processing mechanisms.     

Synaptic mechanisms in invertebrate pattern generation

Although individual neurons can be intrinsically oscillatory and can be network pacemakers, motor patterns are often generated in a more distributed manner. Synaptic connections with other neurons are important because they either modify the rhythm of the pacemaker cell or are essential for pattern generation in the first place. Computational studies of half-center oscillators have made much progress in describing how neurons make transitions between active and inactive phases in these simple networks. In addition to characterizing phase transitions, recent studies have described the synaptic mechanisms that are important for the initiation and maintenance of activity in half-center oscillators.