Biology subjects

Gruart, A.

Publications and source records attributed to Gruart, A..

5 recordsLinked to original sources

bioRxiv2021

Behavioral deficits, learning impairment, and enhanced hippocampal excitability in co-isogenic PrnpZH3/ZH3 mice

BackgroundThe cellular prion protein (PrPC) has been associated with numerous cellular processes, such as cell differentiation and neurotransmission. Moreover, it was recently demonstrated that some functions were misattributed to PrPC since results were obtained from mouse models with genetic artifacts. Here we elucidate the role of PrPC in the hippocampal circuitry and its related functions, like learning and memory, using the new strictly co-isogenic Prnp0/0 mouse (PrnpZH3/ZH3). Behavioral and operant conditioning tests were performed to evaluate memory and learning capabilities. In vivo electrophysiological recordings were carried out at CA3-CA1 synapses in living behaving mice, and spontaneous neuronal firing and network formation were monitored in primary neuronal cultures of PrnpZH3/ZH3 vs. wild-type mice. ResultsResults showed decreased motility, impaired operant conditioning learning, and anxiety-related behavior in PrnpZH3/ZH3 animals. PrPC absence enhanced susceptibility to high-intensity stimulations and kainate-induced seizures. However, long-term potentiation (LTP) was not enhanced in the PrnpZH3/ZH3 hippocampus. In addition, we observed a delay in neuronal maturation and network formation in PrnpZH3/ZH3 cultures. ConclusionIn conclusion, PrPC mediates synaptic function and protects the synapse from excitotoxic insults. Its deletion might evoke a susceptible epileptogenic brain that would fail to perform highly cognitive-demanding tasks such as associative learning and anxiety-like behaviors.

neuroscience↗

bioRxiv2020

Coexistence of amyloid-β and Tau hyperphosphorylation rescues cognitive and electrophysiological deficiencies in a mouse model of Alzheimer's disease

Alzheimers disease comprises amyloid-{beta} (A{beta}) and hyperphosphorylated Tau (P-Tau) accumulation, imbalanced neuronal activity, aberrant oscillatory rhythms, and cognitive deficits. Non-Demented with Alzheimers disease Neuropathology (NDAN) defines a novel clinical entity with A{beta} and Tau pathologies, but preserved cognition. The mechanisms underlying such neuroprotection remain undetermined and animal models are currently unavailable for NDAN. We show that J20/VLW mice, accumulating A{beta} and P-Tau, exhibit preserved hippocampal rhythmic activity and cognition, altered in J20 and VLW animals. Furthermore, we show that coexistence with A{beta} renders a particular P-Tau signature in hippocampal interneurons. The GABAergic septohippocampal pathway, responsible for hippocampal rhythmic activity, is preserved in J20/VLW mice, in contrast to single mutants. Our data highlight J20/VLW mice as a suitable animal model to understand the mechanisms driving cognitive preservation in NDAN and suggest that a differential P-Tau pattern in hippocampal interneurons prevents GABAergic septohippocampal innervation loss and alterations in local field potentials, avoiding cognitive deficits.

neuroscience↗

bioRxiv2020

Basal G-protein-gated inwardly rectifying potassium (Kir3/GirK) channels activity governs synaptic plasticity that supports dorsal hippocampus-dependent cognitive functions

G-protein-gated inwardly rectifying potassium (Kir3/GirK) channel is the effector of many G-protein-coupled receptors. Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimers and Parkinsons diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. GirK channels are constitutively activated in the dorsal hippocampus contributing to resting membrane potential, and their synaptic activation compensates any excitation excess. Here, in order to elucidate the role of GirK channels activity in the maintenance of dorsal hippocampus-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined. For that purpose, basal GirK activity was pharmacologically modulated by two specific drugs: ML297, a GirK channel opener, and Tertiapin-Q, a GirK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied pharmacological GirK modulation effect on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular injections of both GirK modulators to study their contribution to CA3-CA1 synapse electrophysiological properties, synaptic plasticity, and learning and memory capabilities during hippocampal dependent tasks. We found that pharmacological disruption of basal GirK activity in dorsal hippocampus, causing either function gain or loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GirK activity must take place in the hippocampus to sustain cognitive functions. Significance StatementThe dorsal hippocampus mostly performs cognitive functions related to contextual/spatial associations. These functions rely on synaptic plasticity processes that are critically ruled by a finely tuned neural excitability. Being the downstream physiological effectors of a variety of G-coupled receptors, activation of G protein-gated inwardly rectifying K+ (GirK) channels induces neurons to hyperpolarize, contributing to neural excitability throughout the control of excitatory excess. Here, we demonstrate that modulation of basal GirK channels activity, causing either function gain or loss, transforms HFS-induced LTP into LTD, inducing deficits in dorsal hippocampus-dependent learning and memory. Together, our data show a crucial GirK activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.

neuroscience↗

bioRxiv2020

Immediate and long-term effects of transcranial direct-current stimulation in the mouse primary somatosensory cortex

Transcranial direct-current stimulation (tDCS) is a non-invasive brain stimulation technique consisting in the application of weak electric currents on the scalp. Although previous studies have demonstrated the clinical value of tDCS for modulating sensory, motor, and cognitive functions, there are still huge gaps in the knowledge of the underlying physiological mechanisms. To define the immediate impact as well as the after-effects of tDCS on sensory processing, we first performed electrophysiological recordings in primary somatosensory cortex (S1) of alert mice during and after administration of S1-tDCS, and followed up with immunohistochemical analysis of the stimulated brain regions. During the application of cathodal and anodal transcranial currents we observed polarity-specific bidirectional changes in the N1 component of the sensory-evoked potentials (SEPs) and associated gamma oscillations. Regarding the long-term effects observed after 20 min of tDCS, cathodal stimulation produced significant after-effects including a decreased SEP amplitude for up to 30 min, a power reduction in the 20-80 Hz range and a decrease in gamma event related synchronization (ERS). In contrast, no significant long-term changes in SEP amplitude or power analysis were observed after anodal stimulation except for a significant increase in gamma ERS after tDCS cessation. The polarity-specific differences of these long-term effects were corroborated by immunohistochemical analysis, which revealed an unbalance of GAD 65-67 immunoreactivity between the stimulated vs. non-stimulated S1 region only after cathodal tDCS. These results highlight the differences between immediate and long-term effects of tDCS, as well as the asymmetric long-term changes induced by anodal and cathodal stimulation. Significance StatementHere we provide a first glimpse at the immediate and long-term impact of tDCS on neural processing in alert animals. The obtained results highlight the complexity of tDCS-associated effects, which include both bidirectional as well as asymmetrical modulation depending on the polarity of the stimulation. This asymmetry suggests the implication of different mechanisms underlying the long-term effects induced by anodal and cathodal transcranial currents. Identifying and defining these effects and its associated mechanisms is crucial to help design effective protocols for clinical applications.

neuroscience↗

bioRxiv2020

Lack of astrocytic glycogen alters synaptic plasticity but not seizure susceptibility

Brain glycogen is mainly stored in astrocytes. However, recent studies both in vitro and in vivo indicate that glycogen also plays important roles in neurons. By conditional deletion of glycogen synthase (GYS1), we previously developed a mouse model entirely devoid of glycogen in the central nervous system (GYS1Nestin-KO). These mice displayed altered electrophysiological properties in the hippocampus and increased susceptibility to kainate-induced seizures. To understand which of these functions is related to astrocytic glycogen, in the present study we generated a mouse model in which glycogen synthesis is eliminated specifically in astrocytes (GYS1Gfap-KO). Electrophysiological recordings of awake behaving mice revealed alterations in input/output curves and impaired long-term potentiation, similar, but to a lesser extent, to those obtained with GYS1Nestin-KO mice. Surprisingly, GYS1Gfap-KO mice displayed no change in susceptibility to kainate-induced seizures as determined by fEPSP recordings and video monitoring. These results confirm the importance of astrocytic glycogen in synaptic plasticity.

biochemistry↗