Neuroscience
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Prefrontal cortex (PFC)-related functions, such as working memory (WM) and cognitive flexibility (CF), are among the first to be altered at early stages of Alzheimer's disease (AD). Likewise, transgenic AD models carrying different AD-related mutations, mostly linked to the overproduction of amyloid beta (Aβ) and other peptides, show premature behavioral and functional symptoms associated with PFC alterations. However, little is known about the effects of intracerebral or intra-PFC Aβ infusion on WM and CF, as well as on pyramidal cell excitability and plasticity. ⋯ The inhibition of WM performance was reproduced more potently by a single PFC Aβ infusion and was associated with Aβ accumulation. This behavioral disruption was related to increased layer V pyramidal cell firing, larger sag membrane potential, increased fast after-hyperpolarization and a failure to sustain synaptic long-term potentiation, even leading to long-term depression, at both the hippocampal-PFC pathway and intracortical synapses. These findings show that Aβ can affect PFC excitability and synaptic plasticity balance, damaging PFC-dependent functions, which could constitute the foundations of the early alterations in executive functions in AD patients.
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Endocytosis of GluA2-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in CA1 of the hippocampus regulates forgetting; deficits in forgetting nociceptive memory can induce serious stress disorders. As a transporter of GluA2-containing AMPAR, the functions of glutamate receptor interacting protein 1 (GRIP1) in forgetting and possible stress responses remain unclear. Lentivirus-mediated interference of GRIP1 expression or function in the dorsal CA1 of the hippocampus in mice indicated that GRIP1 overexpression enhanced spatial memory, impaired forgetting in a Barnes maze, and induced anxiety-like behavior in the open field and elevated plus-maze test. ⋯ In vitro experiments showed that GRIP1-ov and -dn, inhibition of PDZ2 and PDZ4/5 domains of GRIP1, and GluA2-dn decreased glycine-induced GluA1 and GluA2 exocytosis; meanwhile, GRIP1-ov and -dn, and interference of PDZ2 and PDZ4/5 domains of GRIP1 blocked AMPA- and NMDA-induced GluA1 and GluA2 endocytosis. Overall, these results suggest that GRIP1 drives AMPA receptor endocytosis and exocytosis bidirectionally; furthermore, GRIP1-induced stabilization of anchoring postsynaptic GluA1 and GluA2 impairs forgetting and induces anxiety-like behavior. GRIP1 may provide a potential therapeutic target in posttraumatic syndromes and anxiety disorders.
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NMDA-type glutamate receptors play a critical role in activity-dependent neurite growth. We employed cell type-specific genetic labeling in zebrafish to examine the effects of NMDA receptor antagonism on the morphological development of tectal pyramidal neurons (PyrNs). ⋯ Axons that synapse with PyrNs, but not on spines, are unaffected by MK801 treatment. These findings may reflect different roles for NMDARs during the development of spiny and aspiny dendrites.
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Major Depressive Disorder (MDD) is an affective disorder typically accompanied by sleep disturbances. Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) is an emerging intervention for treatment-resistant depression, but its effect on sleep has not been closely examined. Here we aimed to characterise sleep deficits in the Flinders sensitive line, an established rodent model of depression, and investigate the consequences of MFB stimulation on sleep-related phenotypes. ⋯ Diverse abnormalities in Flinders sensitive line rats emphasise slow wave sleep as a state of dysfunction in affective disorders. MFB stimulation is able to affect behaviour and sleep physiology without influencing sleep architecture. Gamma modulation may represent a component of antidepressant mechanism.