The effects of chronic glucocorticoid exposure on dendritic length, synapse numbers and glial volume in animal models: Implications for hippocampal volume reductions in depression

Glucocorticoids (GCs) are hormones secreted by the adrenal glands as an endocrine response to stress. Although the main purpose of GCs is to restore homeostasis when acutely elevated, animal studies indicate that chronic exposure to these hormones can cause damage to the hippocampus. This is indicated by reductions in hippocampal volume, and changes in neuronal morphology (i.e., decreases in dendritic length and number of dendritic branch points) and ultrastructure (e.g., smaller synapse number). Smaller hippocampal volume has been also reported in humans diagnosed with major depressive disorder or Cushing's disorder, conditions in which GCs are endogenously and chronically elevated. Although a number of studies considered neuron loss as the major factor contributing to the volume reduction, recent findings indicated that this is not the case. Instead, alterations in dendritic, synaptic and glial processes have been reported. The focus of this paper is to review the GC effects on the cell number, dendritic morphology and synapses in an effort to better understand how these changes may contribute to reductions in hippocampal volume. Taken together, the data from animal models suggest that hippocampal volumetric reductions represent volume loss in the neuropil, which, in turn, under-represent much larger losses of dendrites and synapses.     

Effects of changes in extracellular potassium,magnesium and calcium concentration on synaptic transmission in area CA1 and the dentate gyrus of rat hippocampal slices

The dependence of stimulus-induced synaptic potentials on changes of extracellular ionic concentrations of potassium ([K⁺]_o 3, 5, 8 mM), magnesium ([Mg²⁺]_o 2, 4, 8 mM) and calcium [Ca²⁺]_o (2 mM and continuous lowering by washing with Ca²⁺-free solutions) was investigated in area CA1 and dentate gyrus of rat hippocampal slices. Field potentials (fps), [K⁺]_o and [Ca²⁺]_o were measured with double-barreled ion selective/reference microelectrodes. Paired pulse stimulation (interval 50-ms) was applied either to the lateral perforant path or to the Schaffer collaterals. Elevation of [K⁺]_o from 5 to 8 mM and of [Mg²⁺]_o from 2 to 8 mM depressed the rise of excitatory postsynaptic potentials, as well as the amplitude of population spikes. With elevation of [K⁺]_o, the effect was stronger in the dentate gyrus, while with elevation of [Mg²⁺]_o, the reduction was more pronounced in area CA1. During washout of Ca²⁺, synaptic potentials became reduced and finally depressed. The [Ca²⁺]_o at which synaptic transmission was blocked increased with higher [Mg²⁺]_o and decreased with a change of [K⁺]_o from 3 to 5 mM, whereas with an elevation of [K⁺]_o from 5 to 8 mM, it rose in area CA1 but was reduced in dentate gyrus. All ionic changes also affected frequency habituation and potentiation in paired pulse experimentes. In dentate gyrus, frequency habituation was reversed to frequency potentiation with moderate lowering of [Ca²⁺]_o and with elevation of [Mg²⁺]_o and [K⁺]_o. In contrast, in area CA1 frequency potentiation was reduced upon elevation of [K⁺]_o.     

Altered expression and localization of hippocampal A-type potassium channel subunits in the pilocarpine-induced model of temporal lobe epilepsy

Altered ion channel expression and/or function may contribute to the development of certain human epilepsies. In rats, systemic administration of pilocarpine induces a model of human temporal lobe epilepsy, wherein a brief period of status epilepticus (SE) triggers development of spontaneous recurrent seizures that appear after a latency of 2-3 weeks. Here we investigate changes in expression of A-type voltage-gated potassium (Kv) channels, which control neuronal excitability and regulate action potential propagation and neurotransmitter release, in the pilocarpine model of epilepsy. Using immunohistochemistry, we examined the expression of component subunits of somatodendritic (Kv4.2, Kv4.3, KChIPl and KChIP2) and axonal (Kv1.4) A-type Kv channels in hippocampi of pilocarpine-treated rats that entered SE. We found that Kv4.2, Kv4.3 and KChIP2 staining in the molecular layer of the dentate gyrus changes from being uniformly distributed across the molecular layer to concentrated in just the outer two-thirds. We also observed a loss of KChIP1 immunoreactive interneurons, and a reduction of Kv4.2 and KChIP2 staining in stratum radiatum of CA1. These changes begin to appear 1 week after pilocarpine treatment and persist or are enhanced at 4 and 12 weeks. As such, these changes in Kv channel distribution parallel the acquisition of recurrent spontaneous seizures as observed in this model. We also found temporal changes in Kv1.4 immunoreactivity matching those in Timm's stain, being expanded in stratum lucidum of CA3 and in the inner third of the dentate molecular layer. Among pilocarpine-treated rats, changes were only observed in those that entered SE. These changes in A-type Kv channel expression may contribute to hyperexcitability of dendrites in the associated hippocampal circuits as observed in previous studies of the effects of pilocarpine-induced SE.     

Decreased levels of disrupted-in-schizophrenia 1 (DISC1) are associated with expansion of the dentate granule cell layer in normal and kindled rats

Disrupted-in-schizophrenia 1 (DISC1) is a candidate gene involved in the pathogenesis of schizophrenia. DISC1 expression is particularly abundant in the adult dentate gyrus, in which decreased levels lead to aberrant growth, impaired migration, and accelerated integration of adult generated neurons. Because seizures can also result in similar changes, we tested the hypothesis that DISC1 expression may be altered in an animal model of epilepsy. We found that extended amygdala kindling (i.e., 99-electrical stimulations) significantly decreased DISC1 labeling in the dentate granule cell layer and subgranular zone. Extended kindling also led to an increase in the number of ectopic granule cells in the hilus. In addition, although the width of the granule cell layer was not generally affected by kindling, decreased levels of DISC1 in the subgranular zone and granule cell layer were associated with an expansion of the upper blade and crest of the dentate gyrus in both normal and kindled rats. These novel findings suggest that seizure activity affects DISC1 signaling in the dentate gyrus and that DISC1 expression may regulate the cytoarchitectural organization of the granule cell layer.     

Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1

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A putative link of PUFA, GPR40 and adult-born hippocampal neurons for memory

Long chain polyunsaturated fatty acids (PUFA) such as docosahexaenoic and arachidonic acids, which are enriched in the brain, are important for multiple aspects of neuronal development and function including neurite outgrowth, signal transduction and membrane fluidity. Recent studies show that PUFA are capable of improving hippocampal long-term potentiation, learning ability of aged rats, and cognitive function of humans with memory deficits, although the underlying mechanisms are unknown. There have been several reports studying physiological roles of G-protein coupled receptor 40 (GPR40) in the pancreas, but no studies have focused on the function of GPR40 in the brain. As GPR40 was recently identified in neurons throughout the brain, it is probable that certain PUFA may act, as endogenous ligands, on GPR40 at their cell surface. However, the effects of PUFA upon neuronal functions are still not clearly understood. Here, although circumferential, a combination of in vitro and in vivo data is introduced to consider the effects of docosahexaenoic and arachidonic acids on brain functions. GPR40 was found in the newborn neurons of the normal and postischemic hippocampi of adult macaque monkeys, while the positive effects of PUFA upon Ca(2+) mobilization and cognitive functions were demonstrated in both GPR40 gene-transfected PC12 cells and human subjects with memory deficits. The purpose of this review is to propose a putative link among PUFA, GPR40, and hippocampal newborn neurons by discussing whether PUFA can improve memory functions through GPR40 activation of adult-born neurons. At present, little is known about PUFA requirements that make possible neurogenesis in the adult hippocampus. However, the idea that 'PUFA-GPR40 interaction might be crucial for adult neurogenesis and/or memory' should be examined in detail using various experimental paradigms.