Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington's disease model.
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ABSTRACT:
SUBMITTER: Giralt A
PROVIDER: S-EPMC5459995 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Somatostatin-expressing interneurons (SOM-INs) are a major subpopulation of GABAergic cells in CA1 hippocampus that receive excitation from pyramidal cells (PCs), and, in turn, provide feedback inhibition onto PC dendrites. Excitatory synapses onto SOM-INs show a Hebbian long-term potentiation (LTP) mediated by type 1a metabotropic glutamate receptors (mGluR1a) that is implicated in hippocampus-dependent learning. The neuropeptide somatostatin (SST) is also critical for hippocampal long-term synaptic plasticity, as well as learning and memory. SST effects on hippocampal PCs are well documented, but its actions on inhibitory interneurons remain largely undetermined. In the present work, we investigate the involvement of SST in long-term potentiation of CA1 SOM-IN excitatory synapses using pharmacological approaches targeting the somatostatinergic system and whole cell recordings in slices from transgenic mice expressing eYFP in SOM-INs. We report that application of exogenous SST14 induces long-term potentiation of excitatory postsynaptic potentials in SOM-INs via somatostatin type 1-5 receptors (SST1-5Rs) but does not affect synapses of PC or parvalbumin-expressing interneurons. Hebbian LTP in SOM-INs was prevented by inhibition of SSTRs and by depletion of SST by cysteamine treatment, suggesting a critical role of endogenous SST in LTP. LTP of SOM-IN excitatory synapses induced by SST14 was independent of NMDAR and mGluR1a, activity-dependent, and prevented by blocking GABAA receptor function. Our results indicate that endogenous SST may contribute to Hebbian LTP at excitatory synapses of SOM-INs by controlling GABAA inhibition, uncovering a novel role for SST in regulating long-term synaptic plasticity in somatostatinergic cells that may be important for hippocampus-dependent memory processes.
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Project description:N6-methyladenosine (m6A) regulates many aspects of RNA metabolism and is involved in learning and memory processes. Yet, the impact of a dysregulation of post-transcriptional m6A editing on synaptic impairments in neurodegenerative disorders remains unknown. Here we investigated the m6A methylation pattern in the hippocampus of Huntington's disease (HD) mice and the potential role of the m6A RNA modification in HD cognitive symptomatology. m6A modifications were evaluated in HD mice subjected to a hippocampal cognitive training task through m6A immunoprecipitation sequencing (MeRIP-seq) and the relative levels of m6A-modifying proteins (FTO and METTL14) by subcellular fractionation and Western blot analysis. Stereotaxic CA1 hippocampal delivery of AAV-shFTO was performed to investigate the effect of RNA m6A dysregulation in HD memory deficits. Our results reveal a m6A hypermethylation in relevant HD and synaptic related genes in the hippocampal transcriptome of Hdh+/Q111 mice. Conversely, m6A is aberrantly regulated in an experience-dependent manner in the HD hippocampus leading to demethylation of important components of synapse organization. Notably, the levels of RNA demethylase (FTO) and methyltransferase (METTL14) were modulated after training in the hippocampus of WT mice but not in Hdh+/Q111 mice. Finally, inhibition of FTO expression in the hippocampal CA1 region restored memory disturbances in symptomatic Hdh+/Q111 mice. Altogether, our results suggest that a differential RNA methylation landscape contributes to HD cognitive symptoms and uncover a role of m6A as a novel hallmark of HD.
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Project description:The precise contribution of the cadherin-beta-catenin synapse adhesion complex in the functional and structural changes associated with the pre- and postsynaptic terminals remains unclear. Here we report a requirement for endogenous beta-catenin in regulating synaptic strength and dendritic spine morphology in cultured hippocampal pyramidal neurons. Ablating beta-catenin after the initiation of synaptogenesis in the postsynaptic neuron reduces the amplitude of spontaneous excitatory synaptic responses without a concurrent change in their frequency and synapse density. The normal glutamatergic synaptic response is maintained by postsynaptic beta-catenin in a cadherin-dependent manner and requires the C-terminal PDZ-binding motif of beta-catenin but not the link to the actin cytoskeleton. In addition, ablating beta-catenin in postsynaptic neurons accompanies a block of bidirectional quantal scaling of glutamatergic responses induced by chronic activity manipulation. In older cultures at a time when neurons have abundant dendritic spines, neurons ablated for beta-catenin show thin, elongated spines and reduced proportion of mushroom spines without a change in spine density. Collectively, these findings suggest that the cadherin-beta-catenin complex is an integral component of synaptic strength regulation and plays a basic role in coupling synapse function and spine morphology.
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Project description:The phagocytic activity of astrocytes plays an important role in synapse refinement through the elimination of excess synapses during brain development. The adhesion G protein-coupled receptor BAI1/ADGRB1 contributes to phagocytosis in various tissues, including the clearance of apoptotic myoblasts in skeletal muscle and epithelial cells in the intestine. However, the phagocytic function of ADGRB1 in the brain has not been thoroughly investigated. Given that Adgrb1 is highly expressed in astrocytes but not in microglia, we examined changes in astrocyte gene expression resulting from the loss of ADGRB1. RNA-seq analysis revealed that astrocytes lacking ADGRB1 exhibit altered expression of genes associated with cytoskeleton organization and chemotaxis, processes that are required for phagocytosis. Using cultured astrocytes from mice lacking full-length ADGRB1 (Adgrb1exon2-/-) and wildtype (WT) littermates, we found that Adgrb1exon2-/- astrocytes exhibit significantly reduced phagocytic capacity when compared to similarly prepared astrocytes from WT littermates. Immunostaining of astrocytes and pre-synaptic markers showed less engulfed pre-synaptic elements in astrocytes from Adgrb1exon2-/- mutants. Finally, immunostaining of pre-synaptic and post synaptic markers revealed a significantly higher density of excitatory synapses in Adgrb1exon2-/- mutants. These findings highlight the importance of ADGRB1 in synaptic remodeling and raise the possibility that reduced astrocyte-mediated phagocytosis might underlie the behavioral alterations previously observed in Adgrb1exon2-/- mutants, including increased seizure susceptibility and deficits in social memory.
2024-03-19 | GSE255050 | GEO
Project description:Palmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory, synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on the enzymatic activity of Zdhhc5, its localization at the plasma membrane and its C-terminal domain, which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.
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Project description:Presynaptic calcium influx at most excitatory central synapses is carried by both Cav2.1 and Cav2.2 channels. The kinetics and modulation of Cav2.1 and Cav2.2 channels differ and may affect presynaptic calcium influx. We compared release dynamics at CA3/CA1 synapses in rat hippocampus after selective blockade of either channel subtype and subsequent quantal content restoration. Selective blockade of Cav2.1 channels enhanced paired-pulse facilitation, whereas blockade of Cav2.2 channels decreased it. This effect was observed at short (50 msec) but not longer (500 msec) intervals and was maintained during prolonged bursts of presynaptic activity. It did not reflect differences in the distance of the channels from the calcium sensor. The suppression of this effect by preincubation with the G(o/i)-protein inhibitor pertussis toxin suggests instead that high-frequency stimulation relieves inhibition of Cav2.2 by G(o/i), thereby increasing the number of available channels.
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Project description:IntroductionA large amount of literature has indicated that excitatory synaptic transmission plays a crucial role in epilepsy, but the detailed pathogenesis still needs to be clarified.MethodsIn the present study, we used samples from patients with temporal lobe epilepsy, pentylenetetrazole-kindled mice, and Mg2+ -free-induced epileptic cultured hippocampal neurons to detect the expression pattern of STK24. Then, the whole-cell recording was carried out after STK24 overexpression in the Mg2+ -free-induced epileptic cultured hippocampal neurons. In addition, coimmunoprecipitation was performed to detect the association between endogenous STK24 and main subunits of NMDARs and AMPARs in the hippocampus of PTZ-kindled mice.ResultsHere, we reported that STK24 was specifically located in epileptic neurons of human and pentylenetetrazole-kindled mice. Meanwhile, the expression of STK24 was significantly down-regulated in these samples which are mentioned above. Besides, we found that the amplitude of miniature excitatory postsynaptic currents was increased in STK24 overexpressed epileptic hippocampal cultured neurons, which means the excitatory synaptic transmission was changed. Moreover, the coimmunoprecipitation, which further supported the previous experiment, indicated an association between STK24 and the subunits of the NMDA receptor.ConclusionThese findings expand our understanding of how STK24 involved in the excitatory synaptic transmission in epilepsy and lay a foundation for exploring the possibility of STK24 as a drug target.
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