Showing papers by "Jacob Raber published in 2008"

Loss of AKAP150 perturbs distinct neuronal processes in mice

Abstract: A-Kinase Anchoring Proteins (AKAPs) ensure the fidelity of second messenger signaling events by directing protein kinases and phosphatases toward their preferred substrates. AKAP150 brings protein kinase A (PKA), the calcium/calmodulin dependent phosphatase PP2B and protein kinase C (PKC) to postsynaptic membranes where they facilitate the phosphorylation dependent modulation of certain ion channels. Immunofluorescence and electrophysiological recordings were combined with behavioral analyses to assess whether removal of AKAP150 by gene targeting in mice changes the signaling environment to affect excitatory and inhibitory neuronal processes. Mislocalization of PKA in AKAP150 null hippocampal neurons alters the bidirectional modulation of postsynaptic AMPA receptors with concomitant changes in synaptic transmission and memory retention. AKAP150 null mice also exhibit deficits in motor coordination and strength that are consistent with a role for the anchoring protein in the cerebellum. Loss of AKAP150 in sympathetic cervical ganglion (SCG) neurons reduces muscarinic suppression of inhibitory M currents and provides these animals with a measure of resistance to seizures induced by the non-selective muscarinic agonist pilocarpine. These studies argue that distinct AKAP150-enzyme complexes regulate context-dependent neuronal signaling events in vivo.

Role of histamine in short-and long-term effects of methamphetamine on the developing mouse brain

Abstract: With the rise in methamphetamine (MA) use among women of childbearing age, the potential consequences of MA exposure to the developing brain for cognition in adulthood is a major concern. Histamine might mediate these MA effects. Following MA administration in neonatal mice, histamine levels in brain were elevated and the hypothalamic-pituitary-adrenal axis was activated. Co-administration of MA with the H3 receptor agonist immepip antagonized these effects. The effects of MA on histamine levels and on hypothalamic-pituitary-adrenal axis activation at P20 were more pronounced in female than male mice. These sex differences could have contributed to the increased susceptibility of female mice to the detrimental long-term cognitive effects of MA and the H3/H4 antagonist thioperamide. Following behavioral testing, mice neonatally treated with MA or thioperamide showed reduced levels of the dendritic marker microtubule-associated protein 2 in the CA3 region of the hippocampus and the enthorhinal cortex. This was not seen in mice neonatally treated with immepip and MA who did not show cognitive impairments, suggesting that these brain areas might be particularly important for the long-term effects of MA on cognitive function. These data support a role for histamine in the effects of MA on the developing brain.

Effects of 137Cs γ Irradiation on Cognitive Performance and Measures of Anxiety in Apoe−/− and Wild-Type Female Mice

Abstract: Acevedo, S. F., McGinnis, G. and Raber, J. Effects of 137Cs γ Irradiation on Cognitive Performance and Measures of Anxiety of Apoe−/− and Wild-Type Female Mice. Radiat. Res. 170, 422–428 (2008). Mice deficient in apoE (Apoe−/−) can be used to assess the potential role of apoE in the effects of cranial irradiation on hippocampal function. Radiation-induced impairments in hippocampal function may be more pronounced in female Apoe−/− mice and more pronounced in mice irradiated and tested cognitively later in life. To assess this possibility, female wild-type and Apoe−/− mice were irradiated at 6 months of age with 10 Gy 137Cs γ rays and tested cognitively 3 months later. Sham-irradiated wild-type female mice showed enhanced hippocampal-dependent novel location recognition compared to sham-irradiated Apoe−/− female mice. However, cranial irradiation impaired novel location recognition similarly in both genotypes. Cranial irradiation also impaired hippocampal-dependent spatial memory retention similar...

Passive avoidance learning and memory of 56fe sham-irradiated and irradiated human apoe transgenic mice

Abstract: Cranial irradiation is associated with long-term cognitive impairments, including deficits in hippocampus-dependent learning and memory. Not all people exposed to cranial radiation develop cognitive injury, suggesting the involvement of genetic risk factors. There may also be sex differences in susceptibility to develop radiation-induced cognitive injury. The three major human apolipoprotein E (apoE) isoforms are encoded by distinct alleles (epsilon2, epsilon3, and epsilon4). Compared with epsilon3, epsilon4 increases the risk of cognitive impairments following various challenges while epsilon2 provides relative protection. Women are at higher risk to develop Alzheimer's disease (AD) than men, particularly those carrying epsilon4. In previous experiments using male and female mice expressing human apoE-isoforms E2, E3 or E4 under the mouse apoE promoter, we showed that cranial irradiation with 137Cs (10 Gy) results in hippocampus-dependent cognitive impairments that are sex- and apoE-isoform dependent. 137Cs is a form of irradiation often used in the clinical setting. To investigate whether 56Fe irradiation also has sex- and apoE-isoform dependent effects on hippocampus-dependent cognitive function in human apoE mice, we sham-irradiated and irradiated 2-month old male and female human apoE mice at 3 Gy and assessed their performance in a passive avoidance learning and memory test three to five months later.

Transgenic expression of androgen receptors improves spatial memory retention in both sham-irradiated and137Cs γ-irradiated female mice

Abstract: Acevedo, S. F., Tittle, S., Merry, D. E. and Raber, J. Transgenic Expression of Androgen Receptors Improves Spatial Memory Retention in both Sham-Irradiated and 137Cs γ-Irradiated Female Mice. Radiat. Res. 170, 572–578 (2008). Using a water maze, it has been shown that both wild-type and apoE4-expressing female mice are at greater risk of developing age-related hippocampal-dependent impairments in spatial learning and memory than age-matched male mice of the same genotype. In addition, apoE4-expressing female mice were more sensitive to 137Cs γ-radiation-induced impairment in spatial learning and memory than age-matched male mice of the same genotype. These findings imply that androgen receptors (ARs) contribute to spatial learning and memory, posing the question as to whether transgenic expression of AR in female mice might modulate hippocampal-dependent learning and memory under baseline conditions and after local brain irradiation. Hippocampal-dependent novel location recognition was comparabl...

Tfm-AR modulates the effects of ApoE4 on cognition

Abstract: Female mice are more susceptible to apolipoprotein E (apoE4)-induced cognitive deficits than male mice. These deficits can be antagonized by stimulating androgen receptors (ARs). To determine the role of AR in the cognitive effects of apoE4, we backcrossed mutant mice with a naturally occurring defect in the AR [testicular feminization mutant (tfm)] onto the Apoe-/- background to eliminate mouse apoE gene resulting in non-functional AR, and crossed the tfm/Apoe-/- female mice with apoE4 transgenic male mice. We behaviorally compared Apoe-/-, apoE4, tfm, and tfm/apoE4 male mice. Apoe-/-, apoE4, and tfm mice showed hippocampus-dependent novel location recognition but tfm/apoE4 mice did not. In contrast, all groups showed hippocampus-independent novel object recognition. Hippocampus-dependent learning and memory were also assessed in the water maze. In the water maze probe trial following the second day of hidden platform training, Apoe-/- and apoE4 mice showed spatial memory retention, but tfm and tfm/ApoE4 mice did not. In the water maze, probe trial following the third day of hidden platform training, Apoe-/-, apoE4, and tfm/Apoe-/- mice showed spatial memory retention, but tfm mice did not. These data support an important role for AR in protecting against the detrimental effects of apoE4 on hippocampus-dependent learning and memory.