Analysing an allelic series of rare missense variants of CACNA1I in a Swedish schizophrenia cohort.

CACNA1I is implicated in the susceptibility to schizophrenia by large-scale genetic association studies of single nucleotide polymorphisms. However, the channelopathy of CACNA1I in schizophrenia is unknown. CACNA1I encodes CaV3.3, a neuronal voltage-gated calcium channel that underlies a subtype of T-type current that is important for neuronal excitability in the thalamic reticular nucleus and other regions of the brain. Here, we present an extensive functional characterization of 57 naturally occurring rare and common missense variants of CACNA1I derived from a Swedish schizophrenia cohort of more than 10 000 individuals. Our analysis of this allelic series of coding CACNA1I variants revealed that reduced CaV3.3 channel current density was the dominant phenotype associated with rare CACNA1I coding alleles derived from control subjects, whereas rare CACNA1I alleles from schizophrenia patients encoded CaV3.3 channels with altered responses to voltages. CACNA1I variants associated with altered current density primarily impact the ionic channel pore and those associated with altered responses to voltage impact the voltage-sensing domain. CaV3.3 variants associated with altered voltage dependence of the CaV3.3 channel and those associated with peak current density deficits were significantly segregated across affected and unaffected groups (Fisher's exact test, P = 0.034). Our results, together with recent data from the SCHEMA (Schizophrenia Exome Sequencing Meta-Analysis) cohort, suggest that reduced CaV3.3 function may protect against schizophrenia risk in rare cases. We subsequently modelled the effect of the biophysical properties of CaV3.3 channel variants on thalamic reticular nucleus excitability and found that compared with common variants, ultrarare CaV3.3-coding variants derived from control subjects significantly decreased thalamic reticular nucleus excitability (P = 0.011). When all rare variants were analysed, there was a non-significant trend between variants that reduced thalamic reticular nucleus excitability and variants that either had no effect or increased thalamic reticular nucleus excitability across disease status. Taken together, the results of our functional analysis of an allelic series of >50 CACNA1I variants in a schizophrenia cohort reveal that loss of function of CaV3.3 is a molecular phenotype associated with reduced disease risk burden, and our approach may serve as a template strategy for channelopathies in polygenic disorders.

Perceptual enhancement and suppression correlate with V1 neural activity during active sensing.

Perception in multiple sensory modalities is an active process that involves exploratory behaviors. In humans and other primates, vision results from sensory sampling guided by saccadic eye movements. Saccades are known to modulate visual perception, and a corollary discharge signal associated with saccades appears to establish a sense of visual stability. Neural recordings have shown that saccades also modulate activity widely across the brain. To investigate the neural basis of saccadic effects on perception, simultaneous recordings from multiple neurons in area V1 were made as animals performed a contrast detection task. Perceptual and neural measures were compared when the animal made real saccades that brought a stimulus into V1 receptive fields and when simulated saccades were made (identical retinal stimulation but no eye movement). When real saccades were made and low spatial frequency stimuli were presented, we observed a reduction in both perceptual sensitivity and neural activity compared with simulated saccades; conversely, with higher spatial frequency stimuli, saccades increased visual sensitivity and neural activity. The performance of neural decoders, which used the activity of the population of simultaneously recorded neurons, showed saccade effects on sensitivity that mirrored the frequency-dependent perceptual changes, suggesting that the V1 population activity could support the perceptual effects. A minority of V1 neurons had significant choice probabilities, and the saccades decreased both average choice probability and pairwise noise correlations. Taken together, the findings suggest that a signal related to saccadic eye movements alters V1 spiking to increase the independence of spiking neurons and bias the system toward processing higher spatial frequencies, presumably to enhance object recognition. The effects of saccades on visual perception and noise correlations appear to parallel effects observed in other sensory modalities, suggesting a general principle of active sensory processing.

Transsacadic Information and Corollary Discharge in Local Field Potentials of Macaque V1.

Approximately three times per second, human visual perception is interrupted by a saccadic eye movement. In addition to taking the eyes to a new location, several lines of evidence suggest that the saccades play multiple roles in visual perception. Indeed, it may be crucial that visual processing is informed about movements of the eyes in order to analyze visual input distinctly and efficiently on each fixation and preserve stable visual perception of the world across saccades. A variety of studies has demonstrated that activity in multiple brain areas is modulated by saccades. The hypothesis tested here is that these signals carry significant information that could be used in visual processing. To test this hypothesis, local field potentials (LFPs) were simultaneously recorded from multiple electrodes in macaque primary visual cortex (V1); support vector machines (SVMs) were used to classify the peri-saccadic LFPs. We find that LFPs in area V1 carry information that can be used to distinguish neural activity associated with fixations from saccades, precisely estimate the onset time of fixations, and reliably infer the directions of saccades. This information may be used by the brain in processes including visual stability, saccadic suppression, receptive field (RF) remapping, fixation amplification, and trans-saccadic visual perception.