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IntroductionThe widespread deposition of amyloid beta (Aβ) plaques in late-stage Alzheimer’s disease (AD) is well defined and confirmed byin vivopositron emission tomography (PET). However, there are discrepancies between which regions contribute to the earliest topographical Aβ deposition within the neocortex.MethodsThis study investigated Aβ signals in the peri-threshold SUVr range using Pittsburgh compound B (PiB) PET in a population-based study cross-sectionally and longitudinally. PiB-PET scans from 1,088 participants were assessed to determine the early patterns of PiB loading in the neocortex.ResultsEarly-stage Aβ loading is seen first in the temporal, cingulate, and occipital regions. Regional early deposition patterns are similar in both Apolipoprotein ε4 (APOE) carriers and non-carriers. Hierarchical clustering analysis shows groups with different patterns of early amyloid deposition.DiscussionThese finding of initial Aβ deposition patterns may be of significance for diagnostics and understanding the development of different AD phenotypes.

Specific memory processes and neurological disorders can be ascribed to different dorsoventral regions of the hippocampus. Recently, differences in the anatomical and physiological properties between dorsal and ventral hippocampal CA1 neurons were described for both the rat and mouse hippocampus and have greatly contributed to our understanding of these processes. While differences in the subthreshold properties were similar between rat and mouse neurons, differences in action potential output between dorsal and ventral neurons were strikingly less divergent in mouse compared with rat CA1 neurons. Here, we investigate the mechanism underlying the lack of difference in action potential firing between dorsal and ventral CA1 pyramidal neurons in mouse hippocampus. Consistent with rat, we found that ventral CA1 neurons had a more depolarized resting membrane potential and higher input resistance than dorsal CA1 neurons in the mouse hippocampus. Despite these differences, action potential output in response to current injection was not significantly different. We found that ventral neurons have a more depolarized action potential threshold compared with dorsal neurons and that threshold in ventral neurons was more sensitive to block of KV1 channels compared with dorsal neurons. Outside-out voltage-clamp recordings found that slowly inactivating K+ currents were larger in ventral CA1 neurons. These results suggest that, despite differences in subthreshold properties between dorsal and ventral CA1 neurons, action potential output is normalized by the differential functional expression of D-type K+ channels. NEW & NOTEWORTHY Understanding differences in neurons within a brain region is integral in the reliable interpretation of comparative studies. Our findings identify a novel mechanism by which D-type potassium channels normalize action potential firing between dorsal and ventral CA1 neurons of mouse hippocampus despite differences in subthreshold intrinsic properties. Action potential threshold in ventral neurons is influenced by a greater functional expression of D-type potassium channels resulting in a depolarized action potential threshold compared with dorsal hippocampus.

Fragile X syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism spectrum disorder. Area CA1 of the hippocampus receives current information about the external world from the entorhinal cortex via the temporoammonic (TA) pathway. Given its role in learning and memory, it is surprising that little is known about TA long-term potentiation (TA-LTP) in FXS. We found that TA-LTP was impaired in male fmr1 KO mice. Although there were no significant differences in basal synaptic transmission, synaptically evoked dendritic calcium signals were smaller in KO neurons. Using dendritic recording, we found no difference in complex spikes or pharmacologically isolated Ca(2+) spikes; however, the threshold for fast, Na(+)-dependent dendritic spikes was depolarized in fmr1 KO mice. Cell-attached patch-clamp recordings found no difference in Na(+) channels between wild-type and fmr1 KO CA1 dendrites. Dendritic spike threshold and TA-LTP were restored by blocking A-type K(+) channels with either 150 µm Ba(2+) or the more specific toxin AmmTx3. The impairment of TA-LTP shown here, coupled with previously described enhanced Schaffer collateral LTP, may contribute to spatial memory alterations in FXS. Furthermore, as both of these LTP phenotypes are attributed to changes in A-type K(+) channels in FXS, our findings provide a potential therapeutic target to treat cognitive impairments in FXS. SIGNIFICANCE STATEMENT Alterations in synaptic function and plasticity are likely contributors to learning and memory impairments in many neurologic disorders. Fragile X syndrome is marked by dysfunctional learning and memory and changes in synaptic structure and function. This study shows a lack of LTP at temporoammonic synapses in CA1 neurons associated with biophysical differences in A-type K(+) channels in fmr1 KO CA1 neurons. Our results, along with previous findings on A-type K(+) channel effects on Schaffer collateral LTP, reveal differential effects of a single ion channelopathy on LTP at the two major excitatory pathways of CA1 pyramidal neurons. These findings expand our understanding of memory deficits in FXS and provide a potential therapeutic target for the treatment of memory dysfunction in FXS.