Neuropilin 2/Plexin-A3 receptors regulate the functional connectivity and the excitability in the layers 4 and 5 of the cerebral cortex

The functions of cortical networks are progressively established during development by series of events shaping the neuronal connectivity. Synaptic elimination, which consists of removing the supernumerary connections generated during the earlier stages of cortical development, is one of the latest stages in neuronal network maturation. The semaphorin 3F coreceptors neuropilin 2 (Nrp2) and plexin-A3 (PlxnA3) may play an important role in the functional maturation of the cerebral cortex by regulating the excess dendritic spines on cortical excitatory neurons. Yet, the identity of the connections eliminated under the control of Nrp2/PlxnA3 signaling is debated, and the importance of this synaptic refinement for cortical functions remains poorly understood. Here, we show that Nrp2/PlxnA3 controls the spine densities in layer 4 (L4) and on the apical dendrite of L5 neurons of the sensory and motor cortices. Using a combination of neuroanatomical, ex vivo electrophysiology, and in vivo functional imaging techniques in Nrp2 and PlxnA3 KO mice of both sexes, we disprove the hypothesis that Nrp2/PlxnA3 signaling is required to maintain the ectopic thalamocortical connections observed during embryonic development. We also show that the absence of Nrp2/PlxnA3 signaling leads to the hyperexcitability and excessive synchronization of the neuronal activity in L5 and L4 neuronal networks, suggesting that this system could participate in the refinement of the recurrent corticocortical connectivity in those layers. Altogether, our results argue for a role of semaphorin–Nrp2/PlxnA3 signaling in the proper maturation and functional connectivity of the cerebral cortex, likely by controlling the refinement of recurrent corticocortical connections

Visually Evoked 3–5 Hz Membrane Potential Oscillations Reduce the Responsiveness of Visual Cortex Neurons in Awake Behaving Mice

Low-frequency membrane potential (Vm) oscillations were once thought to only occur in sleeping and anesthetized states. Recently, low-frequency Vm oscillations have been described in inactive awake animals, but it is unclear whether they shape sensory processing in neurons and whether they occur during active awake behavioral states. To answer these questions, we performed two-photon guided whole-cell Vm recordings from primary visual cortex layer 2/3 excitatory and inhibitory neurons in awake mice during passive visual stimulation and performance of visual and auditory discrimination tasks. We recorded stereotyped 3-5 Hz Vm oscillations where the Vm baseline hyperpolarized as the Vm underwent high amplitude rhythmic fluctuations lasting 1-2 s in duration. When 3-5 Hz Vm oscillations coincided with visual cues, excitatory neuron responses to preferred cues were significantly reduced. Despite this disruption to sensory processing, visual cues were critical for evoking 3-5 Hz Vm oscillations when animals performed discrimination tasks and passively viewed drifting grating stimuli. Using pupillometry and animal locomotive speed as indicators of arousal, we found that 3-5 Hz oscillations were not restricted to unaroused states and that they occurred equally in aroused and unaroused states. Therefore, low-frequency Vm oscillations play a role in shaping sensory processing in visual cortical neurons, even during active wakefulness and decision making.SIGNIFICANCE STATEMENT A neuron's membrane potential (Vm) strongly shapes how information is processed in sensory cortices of awake animals. Yet, very little is known about how low-frequency Vm oscillations influence sensory processing and whether they occur in aroused awake animals. By performing two-photon guided whole-cell recordings from layer 2/3 excitatory and inhibitory neurons in the visual cortex of awake behaving animals, we found visually evoked stereotyped 3-5 Hz Vm oscillations that disrupt excitatory responsiveness to visual stimuli. Moreover, these oscillations occurred when animals were in high and low arousal states as measured by animal speed and pupillometry. These findings show, for the first time, that low-frequency Vm oscillations can significantly modulate sensory signal processing, even in awake active animals

Visually Evoked 3–5 Hz Membrane Potential Oscillations Reduce the Responsiveness of Visual Cortex Neurons in Awake Behaving Mice

Low-frequency membrane potential (Vm) oscillations were once thought to only occur in sleeping and anesthetized states. Recently, low-frequency Vm oscillations have been described in inactive awake animals, but it is unclear whether they shape sensory processing in neurons and whether they occur during active awake behavioral states. To answer these questions, we performed two-photon guided whole-cell Vm recordings from primary visual cortex layer 2/3 excitatory and inhibitory neurons in awake mice during passive visual stimulation and performance of visual and auditory discrimination tasks. We recorded stereotyped 3-5 Hz Vm oscillations where the Vm baseline hyperpolarized as the Vm underwent high amplitude rhythmic fluctuations lasting 1-2 s in duration. When 3-5 Hz Vm oscillations coincided with visual cues, excitatory neuron responses to preferred cues were significantly reduced. Despite this disruption to sensory processing, visual cues were critical for evoking 3-5 Hz Vm oscillations when animals performed discrimination tasks and passively viewed drifting grating stimuli. Using pupillometry and animal locomotive speed as indicators of arousal, we found that 3-5 Hz oscillations were not restricted to unaroused states and that they occurred equally in aroused and unaroused states. Therefore, low-frequency Vm oscillations play a role in shaping sensory processing in visual cortical neurons, even during active wakefulness and decision making.SIGNIFICANCE STATEMENT A neuron's membrane potential (Vm) strongly shapes how information is processed in sensory cortices of awake animals. Yet, very little is known about how low-frequency Vm oscillations influence sensory processing and whether they occur in aroused awake animals. By performing two-photon guided whole-cell recordings from layer 2/3 excitatory and inhibitory neurons in the visual cortex of awake behaving animals, we found visually evoked stereotyped 3-5 Hz Vm oscillations that disrupt excitatory responsiveness to visual stimuli. Moreover, these oscillations occurred when animals were in high and low arousal states as measured by animal speed and pupillometry. These findings show, for the first time, that low-frequency Vm oscillations can significantly modulate sensory signal processing, even in awake active animals

Involvement of the thalamic parafascicular nucleus in mesial temporal lobe epilepsy.

International audienceMesial temporal lobe epilepsy (MTLE) is characterized by focal seizures, associated with hippocampal sclerosis, and often resistance to antiepileptic drugs. The parafascicular nucleus (PF) of the thalamus is involved in the generation of physiological oscillatory rhythms. It receives excitatory inputs from the cortex and inhibitory inputs from the basal ganglia, a system implicated in the control of epileptic seizures. The aim of this study was to examine the involvement of the PF in the occurrence of hippocampal paroxysmal discharges (HPDs) in a chronic animal model of MTLE in male mice. We recorded the local field potential (LFP) and the extracellular and intracellular activity of hippocampal and PF neurons during spontaneous HPDs in vivo. The end of the HPDs was concomitant with a slow repolarization in hippocampal neurons leading to an electrical silence. In contrast, it was associated in the PF with a transient increase in the power of the 10-20 Hz band in LFPs and a depolarization of PF neurons resulting in a sustained firing. We tested the role of the PF in the control of HPDs by single 130 Hz electrical stimulation of this nucleus and bilateral intra-PF injection of NMDA and GABA(A) antagonist and agonist. High-frequency PF stimulation interrupted ongoing HPDs at an intensity devoid of behavioral effects. NMDA antagonist and GABA(A) agonist suppressed hippocampal discharges in a dose-dependent way, whereas NMDA agonist and GABA(A) antagonist increased HPDs. Altogether, these data suggest that the PF nucleus plays a role in the modulation of MTLE seizures

Representational untangling by the firing rate nonlinearity in V1 simple cells

An important computational goal of the visual system is “representational untangling” (RU): representing increasingly complex features of visual scenes in an easily decodable format. RU is typically assumed to be achieved in high-level visual cortices via several stages of cortical processing. Here we show, using a canonical population coding model, that RU of low-level orientation information is already performed at the first cortical stage of visual processing, but not before that, by a fundamental cellular-level property: the thresholded firing rate nonlinearity of simple cells in the primary visual cortex (V1). We identified specific, experimentally measurable parameters that determined the optimal firing threshold for RU and found that the thresholds of V1 simple cells extracted from in vivo recordings in awake behaving mice were near optimal. These results suggest that information re-formatting, rather than maximisation, may already be a relevant computational goal for the early visual system.This work was supported by a Lendulet Award of the Hungarian Academy of Sciences (G.O.), an award from the National Brain Research Program of Hungary (NAP-B, KTIA_NAP_12-2-201, GO), and the Wellcome Trust (M.L.), the Whitehall Foundation (P.G) and NIH R01 grant MH105427 (P.G) and the Human Frontier Science Program (RGP0044/2018, P.G.,M.L.,G.O.)

Deep layer somatosensory cortical neurons initiate spike-and-wave discharges in a genetic model of absence seizures.

International audienceTypical absence has long been considered as the prototypic form of generalized nonconvulsive epileptic seizures. Recent investigations in patients and animal models suggest that absence seizures could originate from restricted regions of the cerebral cortex. However, the cellular and local network processes of seizure initiation remain unknown. Here, we show that absence seizures in Genetic Absence Epilepsy Rats from Strasbourg, a well established genetic model of this disease, arise from the facial somatosensory cortex. Using in vivo intracellular recordings, we found that epileptic discharges are initiated in layer 5/6 neurons of this cortical region. These neurons, which show a distinctive hyperactivity associated with a membrane depolarization, lead the firing of distant cortical cells during the epileptic discharge. Consistent with their ictogenic properties, neurons from this "focus" exhibit interictal and preictal oscillations that are converted into epileptic pattern. These results confirm and extend the "focal hypothesis" of absence epilepsy and provide a cellular scenario for the initiation and generalization of absence seizures