John P. Welsh

Is autism due to brain desynchronization

The hypothesis is presented that a disruption in brain synchronization contributes to autism by destroying the coherence of brain rhythms and slowing overall cognitive processing speed. Particular focus is on the inferior olive, a precerebellar structure that is reliably disrupted in autism and which normally generates a coherent 5–13 Hz rhythmic output. New electrophysiological data reveal that the continuity of the rhythmical oscillation in membrane potential generated by inferior olive neurons requires the formation of neuronal assemblies by the connexin36 protein that mediates electrical synapses and promotes neuronal synchrony. An experiment with classical eyeblink conditioning is presented to demonstrate that the inferior olive is necessary to learn about sequences of stimuli presented at intervals in the range of 250–500 ms, but not at 700 ms, revealing that a disruption of the inferior olive slows stimulus processing speed on the time scale that is lost in autistic children. A model is presented in which the voltage oscillation generated by populations of electrically synchronized inferior olivary neurons permits the utilization of sequences of stimuli given at, or faster than, 2 per second. It is expected that the disturbance in inferior olive structure in autism disrupts the ability of inferior olive neurons to become electrically synchronized and to generate coherent rhythmic output, thereby impairing the ability to use rapid sequences of cues for the development of normal language skill. Future directions to test the hypothesis are presented.

Continuous Electrical Oscillations Emerge from a Coupled Network: A Study of the Inferior Olive using Lentiviral Knockdown of Connexin36

Do continuous subthreshold oscillations in membrane potential within an electrically coupled network depend on gap junctional coupling? For the inferior olive (IO), modeling and developmental studies suggested that the answer is yes, although physiological studies of connexin36 knock-out mice lacking electrical coupling suggested that the answer is no. Here we addressed the question differently by using a lentivirus-based vector to express, in the IO of adult rats, a single amino acid mutation of connexin36 that disrupts the intracellular trafficking of wild-type connexin36 and blocks gap junctional coupling. Confocal microscopy of green fluorescence protein-labeled dendrites revealed that the mutant connexin36 prevented wild-type connexin36 from being expressed in dendritic spines of IO neurons. Intracellular recordings from lentivirally transduced IO networks revealed that robust and continuous subthreshold oscillations require gap junctional coupling of IO neuron somata within 40 μm of one another. Topological studies indicated that the minimal coupled network for supporting such oscillations may be confined to the dendritic arbor of a single IO neuron. Occasionally, genetically uncoupled IO neurons showed transient oscillations; however, these were not sustained longer than 3 s and were 69% slower and 71% smaller than the oscillations of normal IO neurons, a finding replicated with carbenoxolone, a pharmacological antagonist of gap junctions. The experiments provided the first direct evidence that gap junctional coupling between neurons, specifically mediated by connexin36, allows a continuous network oscillation to emerge from a population of weak and episodic single-cell oscillators. The findings are discussed in the context of the importance of gap junctions for cerebellar rhythms involved in movement.

Functional Significance of Climbing-Fiber Synchrony

Abstract: Population coding and behavioral approaches were taken toward analyzing the functional significance of the climbing‐fiber system. Analyses of neuronal interaction using the joint peristimulus time histogram showed that given a low rate of firing, the climbing‐fiber system organizes itself to fire synchronously during movement—a feature that bears little or no relationship to the modulation in firing rate during movement or whether olivary neurons respond to a sensory stimulus. Moreover, the climbing‐fiber system avoids synchrony during a passive sensory response but actively makes a transition into synchrony as a movement is initiated. Thus, from a functional viewpoint, the active feature of the climbing‐fiber system to organize into synchronously firing cell ensembles is uniquely motor. Analyses of behaving rats without an inferior olive revealed that the climbing‐fiber system optimizes the timing of skilled movement by reducing reaction time and the interval between repetitive movements by 100 milliseconds. Finally, using classical delay eyeblink conditioning, it was found that the inferior olive is essential for learning about rapid sequences of events but not the same event sequence when given more slowly. It was concluded that the climbing‐fiber system exerts its function through synchrony, which provides a 100 ms advantage in movement speed and the ability to learn about events that are rapidly presented in time.

Independently movable multielectrode array to record multiple fast-spiking neurons in the cerebral cortex during cognition

A multiple microelectrode carrier system is described that allows each of 16 microelectrodes in a high-density array to be manipulated in the brain independently by remote control during a cognitive task. Descriptions of the carrier system, advancing techniques, and microelectrode design are presented that allow high-fidelity, extracellular recordings of multiple cerebral cortex neurons with high signal-to-noise ratio and day-to-day repeatability. The motivation for the new carrier system was to provide a method to target multi-microelectrode recordings to a distinct population of fast-spiking neurons in the cerebral cortex during a behavioral task to assess their involvement in selective attention. Recent work using intracellular recording in vitro and single-neuron extracellular recordings in vivo has demonstrated that subpopulations of cortical interneurons can be identified on the basis of their action potential waveform and response to sensory input, and that such interneurons play a fundamental role in generating cortical rhythmicity associated with vigilant wakefulness. A new behavioral paradigm is presented, based on Pavlovs and Kamins classic work on compound conditioning, that permits the electrophysiological patterns of selective attention among neuronal ensembles to be distinguished from those of sensation without attention in a primary sensory cortex. Our approach of multiple, individually guided cerebral cortical recordings in behaving rats during a complex cognitive task is beginning to provide new support for the role of fast cerebral rhythms in selective attention.

A dominant negative mutation of neuronal connexin 36 that blocks intercellular permeability

Rat connexin 36 (Cx36) was mutated by substituting serine for cysteine at residue 231 (C231S) and the mutants effect on the subcellular localization of wild-type Cx36 and the intercellular permeability that it confers was determined in human HeLa and rat PC12 cells. Cells transfected with the mutant or wild-type Cx36 cDNA expressed the expected 36 kDa protein and Cx36 immunoreactivity. Co-immunoprecipitation experiments with monkey COS-7 cells transiently transfected with both mutant and wild-type Cx36 cDNAs demonstrated that the mutant protein bound to the wild-type. Double immunofluorescence microscopy of stably transfected HeLa cells demonstrated that mutant Cx36 blocked the transport of the wild-type Cx36 to the cell membrane, primarily by trapping it in the endoplasmic reticulum around the nucleus. Coexpression of the mutant Cx36 with the wild-type protein abolished the ability of the latter to permit dye transfer in both HeLa and PC12 cells. The findings are the first demonstration of a mutation of Cx36 that inhibits wild-type Cx36 function in mammalian cells.

The cerebellum as a neuronal prosthesis machine

Publisher Summary This chapter discusses the architecture of the cerebellar cortex, which represents a substrate that can be exploited for controlling skilled movements by a multi-electrode device. The idea may seem futuristic to some, hence, it is buoyed by a number of factors. A multi-electrode stimulation device interfaced to the cerebellum for modulating movement taps into the natural function of the cerebellum to modulate ongoing voluntary movement. Multi-neuron stimulation of visual cortex or the dorsal cochlear nucleus provides vision and audition to peripherally deafferented patients. Combinations of synchronous activation of olivocerebellar clusters provide inertial breaks and asynchronous fast activations to maintain or fine tune position that has to be utilized.