Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance

Neurons derived from human induced pluripotent stem cells (hiPSCs) have been used to model basic cellular aspects of neuropsychiatric disorders, but the relationship between the emergent phenotypes and the clinical characteristics of donor individuals has been unclear. We analyzed RNA expression and indices of cellular function in hiPSC-derived neural progenitors and cortical neurons generated from 13 individuals with high polygenic risk scores (PRSs) for schizophrenia (SCZ) and a clinical diagnosis of SCZ, along with 15 neurotypical individuals with low PRS. We identified electrophysiological measures in the patient-derived neurons that implicated altered Na+ channel function, action potential interspike interval, and gamma-aminobutyric acid–ergic neurotransmission. Importantly, electrophysiological measures predicted cardinal clinical and cognitive features found in these SCZ patients. The identification of basic neuronal physiological properties related to core clinical characteristics of illness is a potentially critical step in generating leads for novel therapeutics.

Synaptic Interactions in Scorpion Peg Sensilla Appear to Maintain Chemosensory Neurons within Dynamic Firing Range

Scorpions have elaborate chemo-tactile organs called pectines on their ventral mesosoma. The teeth of the comb-like pectines support thousands of minute projections called peg sensilla (a.k.a. “pegs”), each containing approximately 10 chemosensory neurons. Males use pectines to detect pheromones released by females, and both sexes apparently use pectines to find prey and navigate to home retreats. Electrophysiological recordings from pegs of Paruroctonus utahensis reveal three spontaneously active cells (A1, A2, and B), which appear to interact synaptically. We made long-term extracellular recordings from the bases of peg sensilla and used a combination of conditional cross-interval and conditional interspike-interval analyses to assess the temporal dynamics of the A and B spike trains. Like previous studies, we found that A cells are inhibited by B cells for tens of milliseconds. However, after normalizing our records, we also found clear evidence that the A cells excite the B cells. This simple local circuit appears to maintain the A cells in a dynamic firing range and may have important implications for tracking pheromonal trails and sensing substrate chemistry for navigation.

Interspike interval correlations in neuron models with adaptation and correlated noise

The generation of neural action potentials (spikes) is random but nevertheless may result in a rich statistical structure of the spike sequence. In particular, contrary to the popular renewal assumption of theoreticians, the intervals between adjacent spikes are often correlated. Experimentally, different patterns of interspike-interval correlations have been observed and computational studies have identified spike-frequency adaptation and correlated noise as the two main mechanisms that can lead to such correlations. Analytical studies have focused on the single cases of either correlated (colored) noise or adaptation currents in combination with uncorrelated (white) noise. For low-pass filtered noise or adaptation, the serial correlation coefficient can be approximated as a single geometric sequence of the lag between the intervals, providing an explanation for some of the experimentally observed patterns. Here we address the problem of interval correlations for a widely used class of models, multidimensional integrate-and-fire neurons subject to a combination of colored and white noise sources and a spike-triggered adaptation current. Assuming weak noise, we derive a simple formula for the serial correlation coefficient, a sum of two geometric sequences, which accounts for a large class of correlation patterns. The theory is confirmed by means of numerical simulations in a number of special cases including the leaky, quadratic, and generalized integrate-and-fire models with colored noise and spike-frequency adaptation. Furthermore we study the case in which the adaptation current and the colored noise share the same time scale, corresponding to a slow stochastic population of adaptation channels; we demonstrate that our theory can account for a nonmonotonic dependence of the correlation coefficient on the channel’s time scale. Another application of the theory is a neuron driven by network-noise-like fluctuations (green noise). We also discuss the range of validity of our weak-noise theory and show that by changing the relative strength of white and colored noise sources, we can change the sign of the correlation coefficient. Finally, we apply our theory to a conductance-based model which demonstrates its broad applicability.

Enhanced Signal Detection by Adaptive Decorrelation of Interspike Intervals

Spike trains with negative interspike interval (ISI) correlations, in which long/short ISIs are more likely followed by short/long ISIs, are common in many neurons. They can be described by stochastic models with a spike-triggered adaptation variable. We analyze a phenomenon in these models where such statistically dependent ISI sequences arise in tandem with quasi-statistically independent and identically distributed (quasi-IID) adaptation variable sequences. The sequences of adaptation states and resulting ISIs are linked by a nonlinear decorrelating transformation. We establish general conditions on a family of stochastic spiking models that guarantee this quasi-IID property and establish bounds on the resulting baseline ISI correlations. Inputs that elicit weak firing rate changes in samples with many spikes are known to be more detectible when negative ISI correlations are present because they reduce spike count variance; this defines a variance-reduced firing rate coding benchmark. We performed a Fisher information analysis on these adapting models exhibiting ISI correlations to show that a spike pattern code based on the quasi-IID property achieves the upper bound of detection performance, surpassing rate codes with the same mean rate—including the variance-reduced rate code benchmark—by 20% to 30%. The information loss in rate codes arises because the benefits of reduced spike count variance cannot compensate for the lower firing rate gain due to adaptation. Since adaptation states have similar dynamics to synaptic responses, the quasi-IID decorrelation transformation of the spike train is plausibly implemented by downstream neurons through matched postsynaptic kinetics. This provides an explanation for observed coding performance in sensory systems that cannot be accounted for by rate coding, for example, at the detection threshold where rate changes can be insignificant.

Quantitative Properties of the Creation and Activation of a Cell-Intrinsic Engram

The conditional pause in the spontaneous firing of the cerebellar Purkinje, which determines the timing of the conditional eyeblink response, is mediated by a cell-intrinsic engram (Johansson, et al. 2014) that encodes the interstimulus interval. Our trial-by-trial analysis of the pause parameters reveals that it consists of a single unusually long interspike interval, whose onset and offset latencies are stochastically independent scalar functions of the interstimulus interval. The coefficients of variation are comparable to those observed in the timing of the overt conditional eyeblink. The onsets of the long interspike interval are step changes; there is no prior build-up of inhibition. A single spike volley in the parallel fiber input triggers the read-out of the engram into the long interspike interval; subsequent volleys have no effect on the pause. The high spontaneous firing rate on which the one-interval firing pause supervenes is markedly non-stationary (Fano factors >> 1).

A121 SILENCING ENTERIC SENSORY NEURONS ABOLISHES THE EXCITATORY EFFECT OF SERTRALINE ON VAGAL AFFERENTS

Background Two thirds of vagal afferents supplying the small intestine terminate on intrinsic primary afferent neurons (IPANs) of the enteric nervous system via intraganglionic laminar endings (IGLEs) rather than the luminal epithelium (FASEB J, 28, 3064–3074, 2014). The IPAN to IGLE connection forms a functional intramural sensory synapse within the myenteric plexus. We have recently shown (Sci Rep, 9, 14290, 2019) that the antidepressant behavioural effects of selective serotonin reuptake inhibitors (SSRIs) are dependent on the vagus nerve and that intraluminal application of the SSRIs fluoxetine and sertraline increase vagal afferent firing rate in vitro. Aims We hypothesize that the vagal afferent response to intraluminal sertraline is mediated by IPAN to IGLE sensory signaling. Methods Mesenteric nerve recordings were performed using 2–3 cm jejunal segments and attached mesentery from 6–8 weeks old male Balb/c mice. Jejunal tissue was pinned out and dissected in a petri dish of Krebs to remove excess mesentery to isolate the mesenteric nerve bundle. Multi-unit electrical activity was recorded by patch-clamp electrode using an amplifier and signal converter by sucking onto the mesenteric nerve bundle with a glass micropipette. Baseline firing was recorded for 30 mins during luminal Krebs perfusion. The vagal afferent firing response to sertraline (10 µM) was measured in the absence or presence of 5 µM of the intermediate conductance calcium-dependent (IKCa) channel opener 5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazole-2-one (DCEBIO) to the serosa to selectively silence IPANs. Dataview software (J Neuroscience Methods, 185, 151, 2009) was used to isolate single unit firing post-hoc. Vagal fibre action potentials were identified by response to CCK. Results Intraluminal sertraline decreased the mean vagal interspike interval (increased vagal firing frequency) by 29% (p = 0.008) compared to Krebs control (N = 15 fibres). In contrast, addition of luminal sertraline in the presence of DCEBIO increased mean vagal interspike interval by 48% (p = 0.0103) compared to Krebs control (N = 12 fibres). Serosal addition of the N-type Ca2+ channel blocker w-Conotoxin GVIA simultaneously with luminal sertraline increased the mean vagal interspike interval by 12% (p = 0.0282) compared to Krebs control (N = 7 fibres). Conclusions Silencing of myenteric IPANs to vagus neurotransmission blocked excitatory response of vagal afferent fibres to intraluminal sertraline. Blocking myenteric neurotransmission reduced the vagus excitatory response to sertraline by more than 50%. These results suggest that the therapeutically necessary vagus nerve stimulation by sertraline involves activation of the myenteric intramural sensory synapse. Funding Agencies NSERC, OGS

Neurophysiological Characterization of Thalamic Nuclei in Epileptic Anaesthetized Patients

Deep brain stimulation (DBS) requires precise localization, which is especially difficult at the thalamus, and even more difficult in anesthetized patients. We aimed to characterize the neurophysiological properties of the ventral intermediate (V.im), ventral caudal (V.c), and centromedian parvo (Ce.pc) and the magnocellular (Ce.mc) thalamic nuclei. We obtained microelectrode recordings from five patients with refractory epilepsy under general anesthesia. Somatosensory evoked potentials recorded by microelectrodes were used to identify the V.c nucleus. Trajectories were reconstructed off-line to identify the nucleus recorded, and the amplitude of the action potential (AP) and the tonic (i.e., mean frequency, density, probability of interspike interval) and phasic (i.e., burst index, pause index, and pause ratio) properties of the pattern discharges were analyzed. The Mahalanobis metric was used to evaluate the similarity of the patterns. The mean AP amplitude was higher for the V.im nucleus (172.7 ± 7.6 µV) than for the other nuclei, and the mean frequency was lower for the Ce.pc nucleus (7.2 ± 0.8 Hz) and higher for the V.c nucleus (11.9 ± 0.8 Hz) than for the other nuclei. The phasic properties showed a bursting pattern for the V.c nucleus and a tonic pattern for the centromedian and V.im nuclei. The Mahalanobis distance was the shortest for the V.im/V.c and Ce.mp/Ce.pc pairs. Therefore, the different properties of the thalamic nuclei, even for patients under general anesthesia, can be used to positively define the recorded structure, improving the exactness of electrode placement in DBS.