Biology subjects

Serrat, R.

Publications and source records attributed to Serrat, R..

4 recordsLinked to original sources

bioRxiv2025

Astrocyte CB1 receptors drive blood-brain barrier disruption in CNS inflammatory disease

Reactive astrocytes shape central nervous system (CNS) inflammation and participate in myelin damage and repair mechanisms in multiple sclerosis (MS). Through the activation of cannabinoid CB1 receptors (CB1R) expressed by neurons and oligodendrocyte lineage cells, endocannabinoid signaling restricts neurodegeneration and promote remyelination in preclinical MS models. However, despite accumulating evidence that supports a crucial role for these receptor populations in brain physiology and pathology, the implications of astrocyte CB1R signaling in MS initiation and progression remain uncertain. Using complementary in vivo disease models, here we investigated the effects of targeted genetic deletion of astrocytes CB1R on the expression of MS-like pathology in mice. Interestingly, astrocyte-specific deletion of CB1R reduced demyelinating neuropathology, attenuated astrocyte reactivity and improved clinical deficits during the time-course of experimental autoimmune encephalomyelitis (EAE). Mice with astrocyte CB1R inactivation displayed unaltered oligodendrocyte populations both in EAE lesions and in lysolecithin-induced remyelinating spinal cord lesions, likely excluding that astrocyte CB1R modulate myelin repair processes. Conversely, inactivation of CB1R in astroglial cells restricted humoral and leukocyte parenchymal infiltration and reduced the expression of vascular effectors in EAE lesions. Finally, loss of blood-brain barrier (BBB) function induced by cortical microinjection of VEGF-A was less severe in GFAP-CB1R-KO mice. These results show that astrocyte CB1R signaling constitutes a significant pro-inflammatory mechanism in MS and bring to light a deleterious role for endocannabinoid-mediated modulation of astroglial cells with potential implications in the etiopathology and therapy of neuroinflammatory disorders.

neuroscience↗

bioRxiv2023

Autoimmune inflammation triggers aberrant astrocytic calcium signaling to impair synaptic plasticity

Cortical pathology involving inflammatory and neurodegenerative mechanisms is a hallmark of multiple sclerosis (MS) and a correlate of disease progression and cognitive decline. Astrocytes play a pivotal role in MS initiation and progression but astrocyte-neuronal network alterations contributing to gray matter pathology remain undefined. Here we measured astrocytic calcium in the experimental autoimmune encephalomyelitis (EAE) model of MS using fiber photometry in freely behaving mice and two-photon imaging ex vivo. We identified the emergence of spontaneously hyperactive cortical astrocytes displaying calcium transients of increased duration as well as dysfunctional responses to cannabinoid, glutamate and purinoreceptor agonists during acute EAE disease. Deficits in astrocyte calcium responses are associated to abnormal signaling by Gi and Gq protein coupled receptors in the inflamed cortex and are partially mirrored in cells activated with pro-inflammatory factors both in vitro and ex vivo thus suggesting cell-autonomous effects of the cortical neuroinflammatory environment. Finally, we show that deregulated astrocyte calcium activity is associated to an enhancement of glutamatergic gliotransmission and a shift of astrocyte-mediated short-term and long-term plasticity mechanisms towards synaptic potentiation. Overall our data identities astrocyte-neuronal network dysfunction as key pathological feature of the inflammatory gray matter that may contribute to MS symptomatology and clinical progression.

neuroscience↗

bioRxiv2023

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes

Control of brain energy metabolism and regulation of synaptic activity through gliotransmission are two important ways, through which astrocytes contribute to mental functions. However, the potential functional and molecular links between these two astrocyte-dependent processes have been scantly explored. Here we show that a lactate-dependent shift of glycolysis underlies the production of the gliotransmitter D-serine by acute activation of astrocyte type-1 cannabinoid (CB1) receptors, thereby gating synaptic and cognitive processes. Acute cannabinoid application causes a CB1 receptor-dependent rapid and reversible increase of lactate production and release in primary astrocyte cultures. As shown before, mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) were impaired in a novel object recognition (NOR) memory task. This phenotype was rescued not only by the gliotransmitter D-serine, but also by its precursor L-serine. Surprisingly, the administration of lactate and of an agonist of the lactate receptor HCAR1 also reverted the memory impairment of GFAP-CB1-KO mice. This rescue effect was abolished by in vivo blockade of the astrocyte-specific phosphorylated pathway (PP), which diverts glycolysis towards L-serine synthesis, suggesting that lactate signaling might promote the accumulation of this amino acid. Consistent with this idea, lactate and HCAR1 agonism increased the co-agonist occupancy of CA1 post-synaptic hippocampal NMDA receptors. This effect of lactate was abolished by blockade of PP. By establishing a mechanistic link between lactate production and signaling, serine availability, synaptic activity and behavior, these results reveal an unforeseen functional connection between energy metabolism and gliotransmission to control cognitive processes.

neuroscience↗

bioRxiv2020

Astroglial calcium transfer from endoplasmic reticulum to mitochondria determines synaptic integration

Intracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is currently unexplored. We found that the activation of astrocyte mitochondrial-associated CB1 receptors (mtCB1) determines MERCs-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through specific mechanisms regulating the activity of the mitochondrial calcium uniporter (MCU) channel. Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the precise dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that genetic exclusion of mtCB1 receptors or specific astroglial MCU inhibition blocks lateral synaptic potentiation, a key example of astrocyte-dependent integration of distant synapses activity. Altogether, these data reveal an unforeseen link between astroglial MERCs and the regulation of brain network functions.

neuroscience↗