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Chronic immobilization stress (CIS) shortens apical dendritic trees of CA3 pyramidal neurons in the hippocampus of the male rat, and dendritic length may be a determinant of vulnerability to stress. Expression of the polysialylated form of neural cell adhesion molecule (PSA-NCAM) in the hippocampal formation is increased by stress, while PSA removal by Endo-neuraminidase-N (endo-N) is known to cause the mossy fibers to defasciculate and synapse ectopically in their CA3 target area. We show here that enzymatic removal of PSA produced a remarkable expansion of dendritic arbors of CA3 pyramidal neurons, with a lesser effect in CA1. This expansion eclipsed the CIS-induced shortening of CA3 dendrites, with the expanded dendrites of both no-stress-endo-N and CIS-endo-N rats being longer than those in no-stress-control rats and much longer than those in CIS-control rats. As predicted by the hypothesis that endo-N-induced dendritic expansion might increase vulnerability to excitotoxic challenge, systemic injection with kainic acid, showed markedly increased neuronal degeneration, as assessed by fluorojade B histochemistry, in rats that had been treated with endo-N compared to vehicle-treated rats throughout the entire hippocampal formation. PSA removal also exacerbated the CIS-induced reduction in body weight and abolished effects of CIS on NPY and NR2B mRNA levels. These findings support the hypothesis that CA3 arbor plasticity plays a protective role during prolonged stress and clarify the role of PSA-NCAM in stress-induced dendritic plasticity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Glutamate is the major fast excitatory amino acid transmitter in the CNS, and exerts its action through receptors that function as ion channels such as NMDA receptors (NMDARs), AMPA receptors (AMPARs), and kainate receptors (KARs), and also through signaling cascades via metabotropic receptors. Of the ionotropic receptors, NMDARs and AMPARs have been extensively studied for decades, while relatively fewer studies have focused on the role of the KARs in the glutamatergic synapse. Despite this, there is considerable experimental data that suggest a major role for KARs in modulating synaptic transmission and plasticity, particularly in the hippocampal formation, as well as an involvement in disease states. KARs mediate most aspects of kainate-induced seizures and excitotoxic cell death, and thus, are a rational drug target for antiepileptic drug discovery. Recent data from human studies have also highlighted a role for KARs in certain psychiatric diseases, such as schizophrenia and major depression, and a recent association of KAR gene variants with response to antidepressants has brought considerable interest in developing a clearer understanding of KAR action in the brain. We have recently found that exposure to stress and stress hormone administration can produce contrasting changes in KAR subunit expression in the rat hippocampus, suggesting that a modification of hippocampal KARs by stress may be a mechanism for predisposing individuals to stress-related psychiatric diseases. Here, we review the anatomical and functional characteristics of hippocampal KARs, their role in synaptic plasticity, their regulation by certain hormones, and briefly review what is known about their involvement in disease states such as epilepsy and depression., (Copyright 2010 Elsevier Inc. All rights reserved.)

AMPA receptors are a major subtype of ionotropic receptors that respond to glutamate. Positive allosteric modulators of AMPA receptors selectively enhance fast excitatory neurotransmission in the brain and increase overall neuronal excitability. In addition to enhancing cognitive performance, S18986 (Servier, France) and other AMPA receptor modulators have also been shown to be neuroprotective. A particularly relevant context for AMPAR modulator studies is during aging because of increased neuronal vulnerability. It is currently unknown if chronic AMPAR modulator treatment can alter the course of brain aging, a process characterized by impairment of cognitive function, reduced neuronal excitability, and increased inflammation in the brain. We examined the behavioral and some relevant CNS effects of chronic S18986 in rats from 14 to 18 months of age. Here we show that chronic, oral administration of S18986 increases locomotor activity and performance in a spatial memory task in aged rodents. In addition, chronic S18986 treatment retards the decline of forebrain cholinergic neurons by roughly 37% and midbrain dopaminergic neurons by as much as 43% during aging and attenuates the age-related increase in the expression of a microglial marker in the hippocampus. These results provide a framework for further studies of the potentially beneficial effects of AMPAR modulators on brain aging.