Biology subjects

Noriega-Prieto, J. A.

Publications and source records attributed to Noriega-Prieto, J. A..

5 recordsLinked to original sources

bioRxiv2023

Bidirectional Modulation Of Synaptic Transmission By Insulin-Like Growth Factor I

Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity, and is an essential factor in learning and memory processes. Indeed, we have demonstrated that IGF-IR activation induces long-term potentiation (LTP) of synaptic transmission (LTPIGF-I) both in the barrel cortex, improving object recognition (Noriega-Prieto et al., 2021), and in the prefrontal cortex, facilitating the extinction of conditioned fear (Maglio et al., 2021). However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of NMDAR-dependent LTP at layer 2/3 PNs of the mouse barrel cortex is favored or prevented by IGF-I (10nM) or IGF-I (7nM), respectively, when IGF-I is applied 1 hour before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10nM IGF-I generates LTP (LTPIGF-I) of the post-synaptic potentials (PSPs) by inducing LTD of the inhibitory post-synaptic currents (IPSCs), 7nM IGF-I generates LTD of the PSPs (LTDIGF-I) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain. SIGNIFICANCE STATEMENTInsulin-like growth factor-I (IGF-I) signalling plays key regulatory roles in multiple processes of brain physiology, such as learning and memory, and brain pathology, such as Alzheimer disease. Yet, the underlying mechanisms remain largely undefined. Here we demonstrate that IGF-I signalling triggers long-term potentiation (LTP) or long-term depression (LTD) of synaptic transmission at cortical synapses in a concentration dependent manner, thus regulating the induction of Hebbian synaptic plasticity. The present work represents an important conceptual advance in our knowledge of the cellular basis of IGF-I signalling in brain function.

neuroscience↗

bioRxiv2023

Distinct endocannabinoids specifically signal to astrocytes and neurons

The endocannabinoid system is an essential intercellular signaling mechanism with a decisive role in many physiological functions of the brain. Endocannabinoids (eCBs), directly acting on presynaptic neuronal CB1 receptors (CB1Rs), can inhibit neurotransmitter release. In addition, they can potentiate adjacent synapses, inducing lateral regulation of synaptic transmission through astrocyte CB1Rs. In contrast to most, if not all, neurotransmitter systems, the eCB system involves two distinct ligands, Anandamide and 2-Arachidonoylglycerol (AEA and 2AG), and a single receptor (CB1R). The physiological meaning of this particularity remains unknown. Here we show that different eCBs are signaling both astrocytes and neurons, inducing distinct and contrasting synaptic regulation. Combining two-photon with a pharmacological and optogenetic approaches and transgenic mice for the synthesis enzyme of both eCBs, we have found that the absence of 2-AG synthesis abolished the inhibitory effect, which was mediated exclusively by neuronal mechanisms. However, the absence of AEA synthesis prevents the lateral potentiation mediated by astrocyte calcium mobilization. Together this indicates that 2-AG signals to neurons, decreasing neurotransmitter release, while AEA signals to astrocytes and induces lateral potentiation. Additionally, AEA synthesis is required for the synaptic potentiation induced by spike-timing-dependent plasticity, as well as astrocyte CB1R, indicating that distinct eCBs-signaling influences neuronal plasticity. We conclude that 2-AG and AEA induce distinct and contrasting synaptic regulation through CB1R in different cell types.

neuroscience↗

bioRxiv2023

Altered calcium signaling in Bergmann glia contributes to Spinocerebellar ataxia type-1

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by an abnormal expansion of glutamine (Q) encoding CAG repeats in the ATAXIN1 (ATXN1) gene and characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. SCA1 shows severe degeneration of cerebellar Purkinje cells (PCs) and activation of Bergmann glia (BG), a type of cerebellar astroglia closely associated with PCs. Using electrophysiological recordings, confocal imaging and chemogenetic approaches, we have investigated the electrical intrinsic and synaptic properties of PCs and the physiological properties of BG in SCA1 mouse model expressing mutant ATXN1 only in PCs. PCs of SCA1 mice displayed lower spontaneous firing rate and larger medium and slow afterhyperpolarization currents (mIAHP and sIAHP) than wildtype mice, whereas the properties of the synaptic inputs were unaffected. BG of SCA1 mice showed higher calcium hyperactivity and gliotransmission, manifested higher frequency of NMDAR-mediated slow inward currents (SICs) in PC. Preventing the BG calcium hyperexcitability of SCA1 mice by loading BG with the calcium chelator BAPTA restored mIAHP and sIAHP and spontaneous firing rate of PCs to similar levels of wildtype mice. Moreover, mimicking the BG hyperactivity by activating BG expressing Gq- DREADDs in wildtype mice reproduced the SCA1 pathological phenotype of PCs, i.e., enhancement of mIAHP and sIAHP and decrease of spontaneous firing rate. These results indicate that the intrinsic electrical properties of PCs, but not their synaptic properties, were altered in SCA1 mice, and that these alterations were associated with the hyperexcitability of BG. Moreover, preventing BG hyperexcitability in SCA1 mice and promoting BG hyperexcitability in wildtype mice prevented and mimicked, respectively, the pathological electrophysiological phenotype of PCs. Therefore, BG plays a relevant role in the dysfunction of the electrical intrinsic properties of PCs in SCA1 mice, suggesting that they may serve as potential targets for therapeutic approaches to treat the spinocerebellar ataxia type 1.

neuroscience↗

bioRxiv2020

IGF-1 facilitates extinction of conditioned fear

Insulin-like growth factor-1 (IGF-1) plays a key role in synaptic plasticity, degenerative diseases, spatial learning, and anxiety-like behavioral processes. While IGF-1 regulates neuronal activity in many areas of the brain, its effect on synaptic plasticity and animal behavior dependent on the prefrontal cortex remain unexplored. Here, we show that IGF-1 induces a long-lasting depression of the medium and slow post-spike afterhyperpolarization (mAHP and sAHP), increasing the excitability of layer 5 pyramidal neurons of the infralimbic cortex. Besides, IGF-1 mediates a long-term depression of both inhibitory and excitatory synaptic transmission that results in a longterm potentiation of the postsynaptic potentials. We demonstrate that these synaptic and intrinsic regulatory processes mediated by IGF-1 favor the fear extinction memory. These results show novel functional consequences of IGF-1 signaling on animal behavior tasks dependent on the prefrontal cortex, revealing IGF-1 as a key element in the control of the fear extinction memory. Impact StatementIGF-1 modulates the neuronal firing and synaptic plasticity in infralimbic cortex, favoring the extinction memory

neuroscience↗

bioRxiv2020

IGF-I Governs Cortical Inhibitory Synaptic Plasticity By Astrocyte Activation

Insulin-like growth factor-I (IGF-I) signaling plays key regulatory roles in multiple processes of brain physiology and pathology. While the direct effects of IGF-I in neurons have been extensively studied, the astrocyte involvement in IGF-I signaling and the consequences on synaptic plasticity and animal behavior remain unknown. Here we show that IGF-I induces the long-term depression (LTD) of inhibitory synaptic transmission in the mouse barrel cortex. This LTD requires the activation of the IGF-I receptor (IGF-IR) in astrocytes, which stimulates astrocyte Ca2+ signaling and the release of ATP/adenosine that in turn activates A2A adenosine receptors at presynaptic inhibitory terminals. Specific deletion of IGF-IR in cortical astrocytes (IGF-IR-/-) impaired the behavioral performance in a whisker discrimination task. These results show novel mechanisms and functional consequences of IGF-I signaling on cortical inhibitory synaptic plasticity and animal behavior, revealing astrocytes as key elements in these processes.

neuroscience↗