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Alzheimer's disease (AD) is the most common type of dementia afflicting the elderly. In addition to the presence of cortical senile plaques and neurofibrillary tangles, AD is characterized at autopsy by extensive degeneration of brainstem locus coeruleus (LC) neurons that provide noradrenergic innervation to cortical neuropil, together with relative stability of dopaminergic neuron number in substantia nigra (SN) and ventral tegmental area (VTA). The present study used design-based stereological methods to assess catecholaminergic neuronal loss in brains of double transgenic female mice that co-express two human mutations associated with familial AD, amyloid precursor protein (APP(swe)) and presenilin-1 (PS1(DeltaE9)). Mice were analyzed at two age groups, 3-6 months and 16-23 months, when deposition of AD-type beta-amyloid (Abeta) plaques occurs in cortical brain regions. Blocks of brain tissue containing the noradrenergic LC nucleus and two nuclei of dopaminergic neurons, the SN and VTA, were sectioned and sampled in a systematic-random manner and immunostained for tyrosine hydroxylase (TH), a specific marker for catecholaminergic neurons. Using the optical fractionator method we found a 24% reduction in the total number of TH-positive neurons in LC with no changes in SN-VTA of aged dtg APP/PS1 mice compared with non-transgenic controls. No significant differences were observed in numbers of TH-positive neurons in LC or SN-VTA in brains of young female dtg APP/PS1 mice compared to their age-matched controls. The findings of selective neurodegeneration of LC neurons in the brains of aged female dtg APP/PS1 mice mimic the neuropathology in the brains of AD patients at autopsy. These findings support the use of murine models of Abeta deposition to develop novel strategies for the therapeutic management of patients afflicted with AD.

Murine models that mimic the neuropathology of Alzheimer's disease (AD) have the potential to provide insight into the pathogenesis of the disease and lead to new strategies for the therapeutic management of afflicted patients. We used magnetic resonance imaging (MRI), design-based stereology, and high performance liquid chromatography (HPLC) to assess the age-related neuropathology in double transgenic mice that overexpress two AD-related proteins--amyloid precursor protein (APP) and presenilin 1 (PS1)--and age- and gender-matched wild-type (WT) controls. In mice ranging in age from 4-28 months, total volumes of the hippocampal formation (V (HF)) and whole brain (V (brain)) were quantified by the Cavalieri-point counting method on a systematic-random sample of coronal T2-weighted MRI images; the same stereological methods were used to quantify V (HF) and V (brain) after perfusion and histological processing. To assess changes in AD-type beta-amyloid (A beta) plaques, sections from the hippocampal formation and amylgdaloid complex of mice aged 5, 12, and 15 months were stained by Congo Red histochemistry. In aged mice with large numbers of amyloid plaques, systematic-random samples of sections were stained by GFAP immunocytochemistry to assess gender and genotype effects on total numbers of astrocytes. In addition, levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and 5-HT metabolites were assayed by HPLC in fresh-frozen samples from neocortex, striatum, hippocampus, and brainstem. We confirmed age-related increases in amyloid plaques, beginning with a few plaques at 5 months of age and increasing densities by 12 and 15 months. At 15 months of age, there were robust genotype effects, but no gender effects, on GFAP-immunopositive astrocytes in the amygdaloid complex and hippocampus. There were no effects on monoamine levels in all brain regions examined, and no volume changes in hippocampal formation or whole brain as quantified on either neuroimages or tissue sections. Strong correlations were present between volume estimates from MRI images and histological sections, with about 85% reduction in mean V (HF) or mean V (brain) between MRI and processed histological sections. In summary, these findings show that the double transgenic expression of AD-type mutations is associated with age-related increases in amyloid plaques and astrocytosis; however, this model does not recapitulate the cortical atrophy or neurochemical changes that are characteristic of AD.

Synaptic function and neuronal organization in the auditory system has been shown to be reactive and malleable to experience. In this regard, deafness has important implications for auditory processing. Although the general blueprint for auditory circuits appears to be established before the onset of hearing, reduced auditory stimulation during postnatal development produces definable pathologic effects on the structural and functional features of synapses, cells, and pathways. Studying these congenital effects can be accomplished in a number of experimental models, but one of the most reliable is that of the deaf white cat. The deaf white cat is a known model of a cochleosaccular degeneration resembling the Scheibe deformity observed in humans. This chapter reviews our current understanding of auditory pathologies consequent to congenital deafness, highlighting observations made in the deaf white cat model. Most significantly, the restorative effects of electrical stimulation on the auditory system by way of cochlear implantation are presented. The available data demonstrate that synaptic organization in the auditory system is highly plastic to environmental influences.

The auditory experience is crucial for the normal development and maturation of brain structure and the maintenance of the auditory pathways. The specific aims of this review are (i) to provide a brief background of the synaptic morphology of the endbulb of Held in hearing and deaf animals; (ii) to argue the importance of this large synaptic ending in linking neural activity along ascending pathways to environmental acoustic events; (iii) to describe how the re-introduction of electrical activity changes this synapse; and (iv) to examine how changes at the endbulb synapse initiate trans-synaptic changes in ascending auditory projections to the superior olivary complex, the inferior complex, and the auditory cortex.

Congenital deafness results in synaptic abnormalities in auditory nerve endings. These abnormalities are most prominent in terminals called endbulbs of Held, which are large, axosomatic synaptic endings whose size and evolutionary conservation emphasize their importance. Transmission jitter, delay, or failures, which would corrupt the processing of timing information, are possible consequences of the perturbations at this synaptic junction. We sought to determine whether electrical stimulation of the congenitally deaf auditory system via cochlear implants would restore the endbulb synapses to their normal morphology. Three and 6-month-old congenitally deaf cats received unilateral cochlear implants and were stimulated for a period of 10–19 weeks by using human speech processors. Implanted cats exhibited acoustic startle responses and were trained to approach their food dish in response to a specific acoustic stimulus. Endbulb synapses were examined by using serial section electron microscopy from cohorts of cats with normal hearing, congenital deafness, or congenital deafness with a cochlear implant. Synapse restoration was evident in endbulb synapses on the stimulated side of cats implanted at 3 months of age but not at 6 months. In the young implanted cats, postsynaptic densities exhibited normal size, shape, and distribution, and synaptic vesicles had density values typical of hearing cats. Synapses of the contralateral auditory nerve in early implanted cats also exhibited synapses with more normal structural features. These results demonstrate that electrical stimulation with a cochlear implant can help preserve central auditory synapses through direct and indirect pathways in an age-dependent fashion. J. Comp. Neurol. 518:2382– 2404, 2010.

Acutely administered N-methyl-D-asparate (NMDA) antagonists are used to model schizophrenia, as measured by impairments in sensorimotor gating reflected in decreases in prepulse inhibition of the startle response (PPI). Aspects of acute NMDA receptor antagonism limit the applications of these models. The aim of this paper is to determine the long-term effects of developmental phencyclidine (PCP) treatment on sensorimotor gating in both male and female rats. Male and female Sprague Dawley rats were injected with PCP (10 mg/kg s.c.) on postnatal days (PN) 7, 9, and 11 and were tested for PPI on PN 32—34. The groups were then divided and some of the animals received a single dose of PCP (10 mg/kg s.c.) on PN 45. The animals were tested again for PPI at approximately 1, 4, and 6 weeks after the treatment. There were no significant effects of neonatal-only treatment. One week after the PN 45 treatment, animals that were treated as neonates and as adolescents (PCP/PCP) were significantly impaired in PPI in both sexes. Male and female PCP/PCP rats also had significant increases in acoustic startle response 4 weeks posttreatment, which subsequently declined. PPI impairments in both sexes recovered over time and the adolescent-only treated females showed significant increases (improvement) in PPI approximately 6 weeks posttreatment. These data suggest that treatment with an NMDA receptor antagonist during adolescence or early adulthood can produce a relatively long-term impairment of PPI (approximately 1 week) and that this effect is more pronounced in male animals.