Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated with increased production of the amyloid ␤ peptide, A␤42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, A␤ peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717 V3 F )-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased A␤ production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of A␤ that is independent of plaque formation.Alzheimer's disease (AD) is a progressive dementing illness in which the brain becomes littered with neuritic amyloid plaques. These plaques are associated with degenerating neuronal processes and consist primarily of fibrillar aggregates of the amyloid ␤ peptide, A␤. A␤ is derived from the amyloid protein precursor (APP), presumably via proteolytic cleavage of APP by ␤-and ␥-secretases (1). The predominant forms of A␤ are 40 (A␤40) or 42 (A␤42) amino acids in length (2). A␤42 and A␤40 appear to be generated in different intracellular compartments, and A␤42 has a greater propensity to selfaggregate into insoluble fibrils than A␤40 (3, 4). Various point mutations in three distinct genes (APP, presenilin 1, presenilin 2) have been linked to autosomal dominant forms of familial AD (FAD). Notably, all of these mutations increase the production of A␤42 (5).Although A␤ has been shown to be neurotoxic in cell culture (6-8), a causal role for A␤ in widespread neuronal degeneration in vivo remains speculative. A particularly controversial question concerns whether A␤-induced neurotoxicity requires deposition of aggregated A␤ into plaques (9-13). Transgenic mice in which full-length FAD-mutant APPs and A␤ are coexpressed at high levels develop typical neuritic amyloid plaques (14-17). However, loss of neurons so far has been identified in only one of these models (18) whereas two others showed no significant neuronal loss despite extensive cerebral A␤ deposition (19,20). No electrophysiological studies have been reported in these models.In the current study, we investigated in transgenic mice what early effects neuronal expression of full-length, FAD-mutant human APP has on the anatomy and physiology of the hippocampus, a central nervous system structure considered crucial for learning and memory. Our study demonstrates that the development ...

Assessing the development of local circuitry in the hippocampus has relied primarily on anatomic studies. Here we take a physiological approach, to directly evaluate the means by which the mature state of connectivity between CA3 and CA1 hippocampal pyramidal cells is established. Using a technique of comparing miniature excitatory postsynaptic currents (mEPSCs) to EPSCs in response to spontaneously occurring action potentials in CA3 cells, we found that from neonatal to adult ages, functional synapses are created and serve to increase the degree of connectivity between CA3-CA1 cell pairs. Neither the probability of release nor mean quantal size was found to change significantly with age. However, the variability of quantal events decreases substantially as synapses mature. Thus in the hippocampus the developmental strategy for enhancing excitatory synaptic transmission does not appear to involve an increase in the efficacy at individual synapses, but rather an increase in the connectivity between cell pairs.

Both observations in humans with disorders of dopaminergic transmission and molecular studies point to an important role for dopamine in olfaction. In this study we found that dopamine receptor activation in the olfactory bulb causes a significant depression of synaptic transmission at the first relay between olfactory receptor neurons and mitral cells. This depression was found to be caused by activation of the D2 subtype of dopamine receptor and was reversible by a specific D2 receptor antagonist. A change in paired-pulse modulation during the depression suggests a presynaptic locus of action. The depression was found to occur independent of synaptic activity. These results provide the first evidence for dopaminergic control of inputs to the main olfactory bulb. The magnitude and locus of dopamine's modulatory capabilities in the bulb suggest important roles for dopamine in odorant processing.

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