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1.
Proc Natl Acad Sci U S A ; 118(35)2021 08 31.
Article in English | MEDLINE | ID: mdl-34453004

ABSTRACT

Postsynaptic N-methyl-D-aspartate receptors (NMDARs) are crucial mediators of synaptic plasticity due to their ability to act as coincidence detectors of presynaptic and postsynaptic neuronal activity. However, NMDARs exist within the molecular context of a variety of postsynaptic signaling proteins, which can fine-tune their function. Here, we describe a form of NMDAR suppression by large-conductance Ca2+- and voltage-gated K+ (BK) channels in the basal dendrites of a subset of barrel cortex layer 5 pyramidal neurons. We show that NMDAR activation increases intracellular Ca2+ in the vicinity of BK channels, thus activating K+ efflux and strong negative feedback inhibition. We further show that neurons exhibiting such NMDAR-BK coupling serve as high-pass filters for incoming synaptic inputs, precluding the induction of spike timing-dependent plasticity. Together, these data suggest that NMDAR-localized BK channels regulate synaptic integration and provide input-specific synaptic diversity to a thalamocortical circuit.


Subject(s)
Excitatory Postsynaptic Potentials , Large-Conductance Calcium-Activated Potassium Channels/metabolism , Neuronal Plasticity , Receptors, N-Methyl-D-Aspartate/metabolism , Somatosensory Cortex/physiology , Synapses/physiology , Animals , Dendrites/physiology , Humans , Ion Transport , Male , Mice , Mice, Inbred C57BL , Neurons/physiology
2.
Elife ; 102021 04 01.
Article in English | MEDLINE | ID: mdl-33792539

ABSTRACT

Insulin-like growth factor-1 (IGF-1) plays a key role in synaptic plasticity, spatial learning, and anxiety-like behavioral processes. While IGF-1 regulates neuronal firing and synaptic transmission in many areas of the central nervous system, its signaling and consequences on excitability, 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 rat infralimbic cortex. Besides, IGF-1 mediates a presynaptic long-term depression of both inhibitory and excitatory synaptic transmission in these neurons. The net effect of this IGF-1-mediated synaptic plasticity is a long-term potentiation of the postsynaptic potentials. Moreover, we demonstrate that IGF-1 favors the fear extinction memory. These results show novel functional consequences of IGF-1 signaling, revealing IGF-1 as a key element in the control of the fear extinction memory.


Subject(s)
Cortical Excitability/drug effects , Extinction, Psychological/drug effects , Fear/drug effects , Insulin-Like Growth Factor I/administration & dosage , Neuronal Plasticity/drug effects , Pyramidal Cells/drug effects , Animals , Conditioning, Classical , Male , Rats , Rats, Sprague-Dawley
3.
Neurobiol Dis ; 153: 105317, 2021 06.
Article in English | MEDLINE | ID: mdl-33639207

ABSTRACT

Epilepsy is a neurological condition associated to significant brain damage produced by status epilepticus (SE) including neurodegeneration, gliosis and ectopic neurogenesis. Reduction of these processes constitutes a useful strategy to improve recovery and ameliorate negative outcomes after an initial insult. SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), has been shown to increase M-current density in neurons, leading to reduced excitability and protection against seizures. For this study, we used 4-5 months old male transgenic C57BL/6 J and FVB/NJ mice expressing near physiological levels of a constitutively active form of the kinase controlled by its endogenous promoter. Here we show that SGK1.1 activation potently reduces levels of neuronal death (assessed using Fluoro-Jade C staining) and reactive glial activation (reported by GFAP and Iba-1 markers) in limbic regions and cortex, 72 h after SE induced by kainate, even in the context of high seizure activity. This neuroprotective effect is not exclusively through M-current activation but is also directly linked to decreased apoptosis levels assessed by TUNEL assays and quantification of Bim and Bcl-xL by western blot of hippocampal protein extracts. Our results demonstrate that this newly described antiapoptotic role of SGK1.1 activation acts synergistically with the regulation of cellular excitability, resulting in a significant reduction of SE-induced brain damage in areas relevant to epileptogenesis.


Subject(s)
Apoptosis/genetics , Gliosis/genetics , Immediate-Early Proteins/genetics , Neurons/metabolism , Protein Serine-Threonine Kinases/genetics , Status Epilepticus/metabolism , Animals , Calcium-Binding Proteins/metabolism , Cell Survival , Excitatory Amino Acid Agonists/toxicity , Glial Fibrillary Acidic Protein/metabolism , Gliosis/metabolism , Gliosis/pathology , Kainic Acid/toxicity , Mice , Mice, Transgenic , Microfilament Proteins/metabolism , Neuroglia/metabolism , Neurons/pathology , Status Epilepticus/chemically induced , Status Epilepticus/pathology
4.
Cereb Cortex ; 30(5): 3184-3197, 2020 05 14.
Article in English | MEDLINE | ID: mdl-31819941

ABSTRACT

Approaches to control epilepsy, one of the most important idiopathic brain disorders, are of great importance for public health. We have previously shown that in sympathetic neurons the neuronal isoform of the serum and glucocorticoid-regulated kinase (SGK1.1) increases the M-current, a well-known target for seizure control. The effect of SGK1.1 activation on kainate-induced seizures and neuronal excitability was studied in transgenic mice that express a permanently active form of the kinase, using electroencephalogram recordings and electrophysiological measurements in hippocampal brain slices. Our results demonstrate that SGK1.1 activation leads to reduced seizure severity and lower mortality rates following status epilepticus, in an M-current-dependent manner. EEG is characterized by reduced number, shorter duration, and early termination of kainate-induced seizures in the hippocampus and cortex. Hippocampal neurons show decreased excitability associated to increased M-current, without altering basal synaptic transmission or other neuronal properties. Altogether, our results reveal a novel and selective anticonvulsant pathway that promptly terminates seizures, suggesting that SGK1.1 activation can be a potent factor to secure the brain against permanent neuronal damage associated to epilepsy.


Subject(s)
Hippocampus/metabolism , Immediate-Early Proteins/genetics , Neurons/metabolism , Protein Serine-Threonine Kinases/genetics , Seizures/genetics , Status Epilepticus/genetics , Alternative Splicing , Animals , Electroencephalography , Excitatory Amino Acid Agonists/toxicity , Hippocampus/drug effects , Hippocampus/physiopathology , Immediate-Early Proteins/metabolism , KCNQ2 Potassium Channel/metabolism , KCNQ3 Potassium Channel/metabolism , Kainic Acid/toxicity , Mice , Mice, Transgenic , Protein Isoforms , Protein Serine-Threonine Kinases/metabolism , Seizures/chemically induced , Seizures/metabolism , Seizures/physiopathology , Status Epilepticus/chemically induced , Status Epilepticus/metabolism , Status Epilepticus/physiopathology
6.
Psychopharmacology (Berl) ; 229(1): 41-50, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23579428

ABSTRACT

RATIONALE: Repeated cocaine administration induces behavioral sensitization in about 50 % of treated animals. Nitric oxide could be involved in the acquisition and maintenance of behavioral cocaine effects, probably by activation of neuronal nitric oxide synthase (nNOS)/NO/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathway, since inhibition of the nNOS enzyme attenuates development of sensitization in rats. On the other hand, increased cGMP availability by phosphodiesterase 5 inhibitors has been correlated to the misuse and recreational use of these agents and also to the concomitant use with illicit drugs in humans. Hippocampus is an important brain region for conditioning to general context previously associated to drug availability, influencing drug-seeking behavior and sensitization. Moreover, cocaine and other drugs of abuse can affect the strength of glutamate synapses in this structure, lastly modifying neuronal activity in main regions of the reward circuitry. OBJECTIVE: The objective of this study is to determine whether the pharmacological manipulation of nNOS/NO/sGC/cGMP signaling pathway altered changes induced by repeated cocaine exposure. RESULTS: The present investigation showed a relationship between behavioral cocaine sensitization, reduced threshold to generate long-term potentiation (LTP) in hippocampal dentate gyrus, and increased nNOS activity in this structure. However, when nNOS or sGC were inhibited, the number of sensitized animals was reduced, and the threshold to generate LTP was increased. The opposite occurred when cGMP availability was increased. CONCLUSION: We demonstrate a key role of the nNOS activity and NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic transmission.


Subject(s)
Cocaine/administration & dosage , Cyclic GMP/metabolism , Guanylate Cyclase/physiology , Hippocampus/metabolism , Nitric Oxide Synthase Type I/metabolism , Nitric Oxide/metabolism , Phosphodiesterase 5 Inhibitors/pharmacology , Animals , Behavior, Addictive/metabolism , Behavior, Addictive/physiopathology , Guanylate Cyclase/antagonists & inhibitors , Hippocampus/drug effects , Long-Term Potentiation/drug effects , Long-Term Potentiation/physiology , Male , Nitric Oxide Synthase Type I/antagonists & inhibitors , Rats , Rats, Wistar , Signal Transduction/drug effects , Signal Transduction/physiology
7.
Brain Res ; 1097(1): 11-8, 2006 Jun 30.
Article in English | MEDLINE | ID: mdl-16730679

ABSTRACT

Cellular prion protein (PrP(c)) has been associated with some physiological functions in the last few years. In a previous paper, we have demonstrated an increased hippocampal synaptic transmission in adult mice lacking this protein. In the present study, we investigate the impact of aging on the generation and maintenance of hippocampal long-term Potentiation (LTP) in 9-month-old mice devoid of PrP(c) protein (Prnp(0/0)). We observed a lower threshold for inducing LTP in 9-month-old Prnp(0/0) mice compared to wild-type ones at the same age. The maintenance of dentate gyrus LTP was more persistent in hippocampal slices from Prnp(0/0) mice. Furthermore, the expression of mRNA for NR2A and NR2B subunits of the NMDA glutamatergic receptor in hippocampus of aged Prnp(0/0) animals showed an increase compared to the wild type. We propose that increased hippocampal glutamatergic transmission in Prnp(0/0) mice is related to the enhanced plasticity and persistence of the dentate LTP.


Subject(s)
Aging/metabolism , Gene Expression Regulation/physiology , Long-Term Potentiation/physiology , PrPC Proteins/physiology , Aging/genetics , Animals , Hippocampus/physiology , Long-Term Potentiation/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , PrPC Proteins/deficiency , PrPC Proteins/genetics , Receptors, N-Methyl-D-Aspartate/biosynthesis , Receptors, N-Methyl-D-Aspartate/genetics
8.
Brain Res Mol Brain Res ; 131(1-2): 58-64, 2004 Nov 24.
Article in English | MEDLINE | ID: mdl-15530652

ABSTRACT

The cellular prion protein plays a role in the etiology of transmissible and inherited spongiform encephalopathies. However, the physiological role of the cellular prion protein is still under debate. Results regarding the synaptic transmission using the same strain of animals where the cellular prion protein gene was ablated are controversial, and need further investigation. In this work, we have studied the hippocampal synaptic transmission in mice devoid of normal cellular prion protein, and have shown that these animals present an increased excitability in this area by the lower threshold (20 Hz) to generate long-term potentiation (LTP) in hippocampal dentate gyrus when compared to wild-type animals. The mice devoid of normal cellular prion protein are also more sensitive to the blocking effects of dizocilpine and 2-amino-5-phosphonopentanoic acid on the hippocampal long-term potentiation generation. In situ hydridization experiments demonstrated overexpression of the mRNAs for the N-methyl-D-aspartate (NMDA) receptor NR2A and NR2B subunits in mice devoid of normal cellular prion protein. Therefore, our results indicate that these animals have an increased hippocampal synaptic plasticity which can be explained by a facilitated glutamatergic transmission. The higher expression of specific N-methyl-d-aspartate receptor subunits may account for these effects.


Subject(s)
Dentate Gyrus/physiology , Neuronal Plasticity/physiology , PrPC Proteins/genetics , Animals , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Gene Expression , In Situ Hybridization , Long-Term Potentiation/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, N-Methyl-D-Aspartate/genetics
9.
Behav Brain Res ; 136(1): 75-81, 2002 Oct 17.
Article in English | MEDLINE | ID: mdl-12385792

ABSTRACT

Early results from our laboratory have demonstrated a positive correlation between increased hippocampal synaptic plasticity and development of tolerance to hypolocomotive effect of Diazepam (DZ). We have found recently, that pre-exposure to DZ administration context impairs increase of hippocampal synaptic plasticity in conjunction with tolerance to DZ. These findings have suggested, that the tolerance to DZ is context specific. Furthermore, the hippocampus can be critically involved in the behavioral expression of conditioned tolerance to DZ. The results of the present investigation show that animals chronically treated with DZ for 18 days exhibit withdrawal signs, evaluated as an increased anxiety in an elevated plus maze. These animals also show, a facilitation in the threshold to induce long-term potentiation in the hippocampal formation. These phenomena have a strong dependency on the drug administration context, since both are reversed after the introduction of some changes in the drug administration environment. Furthermore, the alteration of some environmental cues increased the locomotive activity in animals that did not show anxiety as a withdrawal signs. We conclude that a common neural system could underlie the behavioral expression of the conditioned tolerance and dependence on DZ.


Subject(s)
Anti-Anxiety Agents/adverse effects , Diazepam/adverse effects , Environment , Substance Withdrawal Syndrome/psychology , Animals , Anxiety/psychology , Cues , Dentate Gyrus/physiology , Electrophysiology , Hippocampus/physiology , In Vitro Techniques , Long-Term Potentiation/drug effects , Male , Motor Activity/physiology , Rats , Synaptic Transmission/physiology
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