Calcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In embryonic mouse cortical neurons using glucose as only fuel, activation by NMDA elicits a strong workload (ATP demand)-dependent on Na+ and Ca2+ entry, and stimulates glucose uptake, glycolysis, pyruvate and lactate production, and oxidative phosphorylation (OXPHOS) in a Ca2+-dependent way. We find that Ca2+ upregulation of glycolysis, pyruvate levels, and respiration, but not glucose uptake, all depend on Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier, component of the malate-aspartate shuttle (MAS). MAS activation increases glycolysis, pyruvate production, and respiration, a process inhibited in the presence of BAPTA-AM, suggesting that the Ca2+ binding motifs in Aralar may be involved in the activation. Mitochondrial calcium uniporter (MCU) silencing had no effect, indicating that none of these processes required MCU-dependent mitochondrial Ca2+ uptake. T...

Cognitive deficits are a major biomedical challenge—and engagement of the brain in stimulating tasks improves cognition in aged individuals ([Wilson et al., 2002][1]; [Gates et al., 2011][2]) and rodents ([Aidil-Carvalho et al., 2017][3]), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biological effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus, and that pharmacologic treatment with the longevity hormone α-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse ...

The molecular mechanisms underlying somatodendritic dopamine (DA) release remain unresolved, despite the passing of decades since its discovery. Our previous work showed robust release of somatodendritic DA in submillimolar extracellular Ca2+ concentration ([Ca2+]o). Here we tested the hypothesis that the high-affinity Ca2+ sensor synaptotagmin 7 (Syt7), is a key determinant of somatodendritic DA release and its Ca2+ dependence. Somatodendritic DA release from SNc DA neurons was assessed using whole-cell recording in midbrain slices from male and female mice to monitor evoked DA-dependent D2 receptor-mediated inhibitory currents (D2ICs). Single-cell application of an antibody to Syt7 (Syt7 Ab) decreased pulse train-evoked D2ICs, revealing a functional role for Syt7. The assessment of the Ca2+ dependence of pulse train-evoked D2ICs confirmed robust DA release in submillimolar [Ca2+]o in wild-type (WT) neurons, but loss of this sensitivity with intracellular Syt7 Ab or in Syt7 knock-out (KO) mice. In millimo...

In human neurodegenerative diseases, neurons undergo axonal degeneration months to years before they die. Here, we developed a system modelling early degenerative events in Drosophila adult photoreceptor cells. Thanks to the stereotypy of their axonal projections, this system delivers quantitative data on sporadic and progressive axonal degeneration of photoreceptor cells. Using this method, we show that exposure of adult female flies to a constant light stimulation for several days overcomes the intrinsic resilience of R7 photoreceptors and leads to progressive axonal degeneration. This was not associated with apoptosis. We furthermore provide evidence that loss of synaptic integrity between R7 and a postsynaptic partner preceded axonal degeneration, thus recapitulating features of human neurodegenerative diseases. Finally, our experiments uncovered a role of postsynaptic partners of R7 to initiate degeneration, suggesting that postsynaptic cells signal back to the photoreceptor to maintain axonal structu...

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson’s disease (PD), but the pathogenic mechanism underlying LRRK2 mutations remains unresolved. In this study, we investigate the consequence of inactivation of LRRK2 and its functional homolog LRRK1 in male and female mice up to 25 months of age using behavioral, neurochemical, neuropathological, and ultrastructural analyses. We report that LRRK1 and LRRK2 double knock-out ( LRRK DKO) mice exhibit impaired motor coordination at 12 months of age before the onset of DA neuron loss in the substantia nigra (SNpc). Moreover, LRRK DKO mice develop age-dependent, progressive loss of DA terminals in the striatum. Evoked dopamine release measured by fast-scan cyclic voltammetry in the dorsal striatum is also reduced in the absence of LRRK. Furthermore, LRRK DKO mice at 20–25 months of age show substantial loss of DA neurons in the SNpc. The surviving SNpc neurons in LRRK DKO mice at 25 months of age accumulate large number...

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 co-receptors 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 layer 5 (L5) neurons of the sensory and motor cortices. Using a combination of neuroanatomical, ex vivo electrophysiology and in vivo functional imagi...

The dynamics of information flow within the auditory cortical hierarchy associated with speech processing and the emergence of hemispheric specialization remain incompletely understood. To study these questions with high spatiotemporal resolution, intracranial recordings in 29 human neurosurgical patients of both sexes were obtained while subjects performed a semantic classification task. Neural activity was recorded from posteromedial and anterolateral portions of Heschl’s gyrus (HGPM, HGAL), planum temporale (PT), planum polare, insula, and superior temporal gyrus (STG). Responses to monosyllabic words exhibited early gamma power increases and a later suppression of alpha power, envisioned to represent feedforward activity and decreased feedback signaling, respectively. Gamma activation and alpha suppression had distinct magnitude and latency profiles. HGPM and PT had the strongest gamma responses with shortest onset latencies, indicating that they are the earliest auditory cortical processing stages. Th...

Excitatory amino acid transporters (EAATs) control visual signal transmission in the retina by rapidly removing glutamate released from photoreceptors and bipolar cells. Although it has been reported that EAAT2 and EAAT5 are expressed at presynaptic terminals of photoreceptors and some bipolar cells in mammals, the distinct functions of these two glutamate transporters in retinal synaptic transmission, especially at a single synapse, remain elusive. In this study we found that EAAT2 was expressed in all bipolar cell types while coexisting with EAAT5 in rod bipolar (RB) cells and several types of cone bipolar cells from mice of either sex. Our immunohistochemical study, together with a recently published literature (Gehlen et al., 2021), showed that EAAT2 and EAAT5 were both located in RB axon terminals near release sites. Optogenetic, electrophysiological and pharmacological analyses, however, demonstrated that EAAT2 and EAAT5 regulated neurotransmission at RB→AII amacrine cell synapses in significantly di...

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder that affects upper and lower motor neurons; however, its pathomechanism has not been fully elucidated. Using a comprehensive phosphoproteomic approach, we have identified elevated phosphorylation of collapsin response mediator protein 1 (Crmp1) at serine 522 in the lumbar spinal cord of ALS model mice overexpressing a human superoxide dismutase mutant (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1G93A mice using Crmp1S522A (Ser522→Ala) knockin ( Crmp1ki/ki ) mice in which the S522 phosphorylation site was abolished and Crmp1 knockout ( Crmp1 -/-) mice, respectively. Crmp1ki/ki/SOD1G93A mice showed longer latency to fall in a rotarod test while Crmp1-/-/SOD1G93A mice showed shorter latency compared with SOD1G93A mice. Survival was prolonged in Crmp1ki/ki/SOD1G93A mice but not in Crmp1-/-/SOD1G93A mice. In agreement with these phenotypic findings, residual motor neurons an...

Recent studies show that the human adult visual system exhibits neural plasticity. For instance, short-term monocular deprivation shifts the eye dominance in favor of the deprived eye. This phenomenon is believed to occur in the primary visual cortex by reinstating neural plasticity. However, it is unknown whether the changes in eye dominance after monocularly depriving the visual input can also be induced by alternately depriving both eyes. In this study, we found no changes in binocular balance and interocular correlation sensitivity after a rapid (7 Hz), alternate and monocular deprivation for one hour in adults. Therefore, the effect of short-term monocular deprivation cannot seem to be emulated by alternately and rapidly depriving both eyes. Significance statement Previous work has shown that short-term binocular function disruption, which its most extreme form is monocular deprivation, could induce neural plasticity in adult visual system. In this study, we found a balanced deprivation of binocula...