6-cyano-7-nitroquinoxaline-2-3-dione and Cognition-Disorders

Neuronal gastrin-releasing peptide (GRP) has been proved to be an important neuromodulator in the brain and involved in a variety of neurological diseases. Whether GRP could attenuate cognition impairment induced by vascular dementia (VD) in rats, and the mechanism of synaptic plasticity and GRP's action on synaptic efficiency are still poorly understood. In this study, we first investigated the effects of GRP on glutamatergic transmission with patch-clamp recording. We found that acute application of GRP enhanced the excitatory synaptic transmission in hippocampal CA1 neurons via GRPR in a presynaptic mechanism. Secondly, we examined whether exogenous GRP or its analogue neuromedin B (NMB) could prevent VD-induced cognitive deficits and the mechanism of synaptic plasticity. By using Morris water maze, long-term potentiation (LTP) recording, western blot assay and immunofluorescent staining, we verified for the first time that GRP or NMB substantially improved the spatial learning and memory abilities in VD rats, restored the impaired synaptic plasticity and was able to elevate the expression of synaptic proteins, synaptophysin (SYP) and CaMKII, which play pivotal roles in synaptic plasticity. These results suggest that the facilitatory effects of GRP on glutamate release may contribute to its long-term action on synaptic efficacy which is essential in cognitive function. Our findings present a new entry point for a better understanding of physiological function of GRP and raise the possibility that GRPR agonists might ameliorate cognitive deficits associated with neurological diseases.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Animals, Newborn; Cognition Disorders; Dementia, Vascular; Disease Models, Animal; Electric Stimulation; Excitatory Postsynaptic Potentials; Gastrin-Releasing Peptide; Glutamic Acid; Hippocampus; In Vitro Techniques; Male; Maze Learning; Nerve Net; Neurokinin B; Rats; Rats, Wistar; Synaptic Transmission; Time Factors

Blast-induced traumatic brain injury (bTBI) and its long term consequences are a major health concern among veterans. Despite recent work enhancing our knowledge about bTBI, very little is known about the contribution of the blast wave alone to the observed sequelae. Herein, we isolated its contribution in a mouse model by constraining the animals' heads during exposure to a shockwave (primary blast). Our results show that exposure to primary blast alone results in changes in hippocampus-dependent behaviors that correspond with electrophysiological changes in area CA1 and are accompanied by reactive gliosis. Specifically, five days after exposure, behavior in an open field and performance in a spatial object recognition (SOR) task were significantly different from sham. Network electrophysiology, also performed five days after injury, demonstrated a significant decrease in excitability and increase in inhibitory tone. Immunohistochemistry for GFAP and Iba1 performed ten days after injury showed a significant increase in staining. Interestingly, a threefold increase in the impulse of the primary blast wave did not exacerbate these measures. However, we observed a significant reduction in the contribution of the NMDA receptors to the field EPSP at the highest blast exposure level. Our results emphasize the need to account for the effects of primary blast loading when studying the sequelae of bTBI.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Biomechanical Phenomena; Brain Injuries; Calcium-Binding Proteins; Cognition Disorders; Disease Models, Animal; Excitatory Amino Acid Antagonists; Exploratory Behavior; Fear; Glial Fibrillary Acidic Protein; Hippocampus; Male; Maze Learning; Membrane Potentials; Mice; Mice, Inbred C57BL; Microfilament Proteins; Motor Activity; Nerve Net; Rotarod Performance Test; Time Factors

Chronic stress could trigger maladaptive changes associated with stress-related mental disorders; however, the underlying mechanisms remain elusive. In this study, we found that exposing juvenile male rats to repeated stress significantly impaired the temporal order recognition memory, a cognitive process controlled by the prefrontal cortex (PFC). Concomitantly, significantly reduced AMPAR- and NMDAR-mediated synaptic transmission and glutamate receptor expression were found in PFC pyramidal neurons from repeatedly stressed animals. All these effects relied on activation of glucocorticoid receptors and the subsequent enhancement of ubiquitin/proteasome-mediated degradation of GluR1 and NR1 subunits, which was controlled by the E3 ubiquitin ligase Nedd4-1 and Fbx2, respectively. Inhibition of proteasomes or knockdown of Nedd4-1 and Fbx2 in PFC prevented the loss of glutamatergic responses and recognition memory in stressed animals. Our results suggest that repeated stress dampens PFC glutamatergic transmission by facilitating glutamate receptor turnover, which causes the detrimental effect on PFC-dependent cognitive processes.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Bicuculline; Cognition Disorders; Disease Models, Animal; Endosomal Sorting Complexes Required for Transport; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; F-Box Proteins; GABA-A Receptor Antagonists; Immunoprecipitation; In Vitro Techniques; Male; Nedd4 Ubiquitin Protein Ligases; Neuropsychological Tests; Prefrontal Cortex; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Recognition, Psychology; Restraint, Physical; RNA, Small Interfering; Stress, Psychological; Ubiquitin-Protein Ligases

Overexpression of GABA(B)R1a receptors in mice (R1a(+)) results in an atypical absence seizure phenotype characterized by 3- to 6-Hz slow spike-and-wave discharges (SSWDs), reduced synaptic plasticity, and cognitive impairment. Here we tested the hypothesis that increased R1 expression causes atypical absence epilepsy and is not subunit specific. GABA(B)R1b receptors were overexpressed in mouse forebrain (R1b(+)) and confirmed by immunoblot and (3)H-CGP54626A autoradiography. The R1b(+) mice showed a reduction in hippocampal long-term potentiation and GABA(A) receptor-mediated inhibitory postsynaptic currents. R1b(+) mice manifested an electrographic, pharmacological, and behavioral phenotype consistent with atypical absence seizures, though less robust than R1a(+) in terms of SSWD duration and severity of cognitive impairment. These results suggest that abnormal GABA(B)R1b function plays a lesser role in the development of atypical absence epilepsy.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Animals, Newborn; Autoradiography; Cognition Disorders; Disease Models, Animal; Electric Stimulation; Electroencephalography; Epilepsy, Absence; Excitatory Amino Acid Antagonists; Hippocampus; In Vitro Techniques; Inhibitory Postsynaptic Potentials; Long-Term Potentiation; Maze Learning; Mice; Mice, Transgenic; Neurons; Organophosphorus Compounds; Patch-Clamp Techniques; Phenotype; Protein Binding; Receptors, GABA-B; Tritium; Valine