Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations.

Disinhibition during early stages of Alzheimer's disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer's disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex. KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-ß 42 (Aß42). Acute administration of Aß42 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer's disease-related cognitive decline. These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer's disease-related cognitive decline; they confirm target engagement, where the therapeutic intervention takes place, and its effectiveness.

Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a fatal disease resulting from motor neuron degeneration in the cortex and spinal cord. Cortical hyperexcitability is a hallmark feature of amyotrophic lateral sclerosis and is accompanied by decreased intracortical inhibition. Using electrophysiological patch-clamp recordings, we revealed parvalbumin interneurons to be hypoactive in the late pre-symptomatic SOD1*G93A mouse model of amyotrophic lateral sclerosis. We discovered that using adeno-associated virus-mediated delivery of chemogenetic technology targeted to increase the activity of the interneurons within layer 5 of the primary motor cortex, we were able to rescue intracortical inhibition and reduce pyramidal neuron hyperexcitability. Increasing the activity of interneurons in the layer 5 of the primary motor cortex was effective in delaying the onset of amyotrophic lateral sclerosis-associated motor deficits, slowing symptom progression, preserving neuronal populations, and increasing the lifespan of SOD1*G93A mice. Taken together, this study provides novel insights into the pathogenesis and treatment of amyotrophic lateral sclerosis.

Understanding the nervous system: lessons from Frontiers in Neurophotonics.

The Frontiers in Neurophotonics Symposium is a biennial event that brings together neurobiologists and physicists/engineers who share interest in the development of leading-edge photonics-based approaches to understand and manipulate the nervous system, from its individual molecular components to complex networks in the intact brain. In this Community paper, we highlight several topics that have been featured at the symposium that took place in October 2022 in Québec City, Canada.

A Wireless Electro-Optic Platform for Multimodal Electrophysiology and Optogenetics in Freely Moving Rodents.

This paper presents the design and the utilization of a wireless electro-optic platform to perform simultaneous multimodal electrophysiological recordings and optogenetic stimulation in freely moving rodents. The developed system can capture neural action potentials (AP), local field potentials (LFP) and electromyography (EMG) signals with up to 32 channels in parallel while providing four optical stimulation channels. The platform is using commercial off-the-shelf components (COTS) and a low-power digital field-programmable gate array (FPGA), to perform digital signal processing to digitally separate in real time the AP, LFP and EMG while performing signal detection and compression for mitigating wireless bandwidth and power consumption limitations. The different signal modalities collected on the 32 channels are time-multiplexed into a single data stream to decrease power consumption and optimize resource utilization. The data reduction strategy is based on signal processing and real-time data compression. Digital filtering, signal detection, and wavelet data compression are used inside the platform to separate the different electrophysiological signal modalities, namely the local field potentials (1-500 Hz), EMG (30-500 Hz), and the action potentials (300-5,000 Hz) and perform data reduction before transmitting the data. The platform achieves a measured data reduction ratio of 7.77 (for a firing rate of 50 AP/second) and weights 4.7 g with a 100-mAh battery, an on/off switch and a protective plastic enclosure. To validate the performance of the platform, we measured distinct electrophysiology signals and performed optogenetics stimulation in vivo in freely moving rondents. We recorded AP and LFP signals with the platform using a 16-microelectrode array implanted in the primary motor cortex of a Long Evans rat, both in anesthetized and freely moving conditions. EMG responses to optogenetic Channelrhodopsin-2 induced activation of motor cortex via optical fiber were also recorded in freely moving rodents.

Functional Interactions of Tau Phosphorylation Sites That Mediate Toxicity and Deficient Learning in Drosophila melanogaster.

Hyperphosphorylated Tau protein is the main component of the neurofibrillary tangles, characterizing degenerating neurons in Alzheimer's disease and other Tauopathies. Expression of human Tau protein in Drosophila CNS results in increased toxicity, premature mortality and learning and memory deficits. Herein we use novel transgenic lines to investigate the contribution of specific phosphorylation sites previously implicated in Tau toxicity. These three different sites, Ser238, Thr245, and Ser262 were tested either by blocking their phosphorylation, by Ser/Thr to Ala substitution, or pseudophosphorylation, by changing Ser/Thr to Glu. We validate the hypothesis that phosphorylation at Ser262 is necessary for Tau-dependent learning deficits and a "facilitatory gatekeeper" to Ser238 occupation, which is linked to Tau toxicity. Importantly we reveal that phosphorylation at Thr245 acts as a "suppressive gatekeeper", preventing phosphorylation of many sites including Ser262 and consequently of Ser238. Therefore, we elucidate novel interactions among phosphosites central to Tau mediated neuronal dysfunction and toxicity, likely driven by phosphorylation-dependent conformational plasticity.

A Wireless Electro-Optic Headstage With a 0.13- µm CMOS Custom Integrated DWT Neural Signal Decoder for Closed-Loop Optogenetics.

We present a wireless electro-optic headstage that uses a 0.13- µm CMOS custom integrated circuit (IC) implementing a digital neural decoder (ND-IC) for enabling real-time closed-loop (CL) optogenetics. The ND-IC processes the neural activity data using three digital cores: 1) the detector core detects and extracts the action potential (AP) of individual neurons by using an adaptive threshold; 2) the data compression core compresses the detected AP by using an efficient Symmlet-2 discrete wavelet transform (DWT) processor for decreasing the amount of data to be transmitted by the low-power wireless link; and 3) the classification core sorts the compressed AP into separated clusters on the fly according to their wave shapes. The ND-IC encompasses several innovations: 1) the compression core decreases the complexity from O(n 2) to O(n · log(n)) compared to the previous solutions, while using two times less memory, thanks to the use of a new coefficient sorting tree; and 2) the AP classification core reuses both the compressed DWT coefficients to perform implicit dimensionality reduction, which allows for performing intensive signal processing on-chip, while increasing power and hardware efficiency. This core also reuses the signal standard deviation already computed by the AP detector core as threshold for performing automatic AP sorting. The headstage also introduces innovations by enabling a new wireless CL scheme between the neural data acquisition module and the optical stimulator. Our CL scheme uses the AP sorting and timing information produced by the ND-IC for detecting complex firing patterns within the brain. The headstage is also smaller (1.13 cm 3), lighter (3.0 g with a 40 mAh battery) and less invasive than the previous solutions, while providing a measured autonomy of 2h40, with the ND-IC. The whole system and the ND-IC are first validated in vivo in the LD thalamus of a Long-Evans rat, and then in freely-moving CL experiments involving a mouse virally expressing ChR2-mCherry in inhibitory neurons of the prelimbic cortex, and the results show that our system works well within an in vivo experimental setting with a freely moving mouse.