Entorhinal cortex volume is associated with episodic memory related brain activation in normal aging and amnesic mild cognitive impairment

The present study examined the relationship between entorhinal cortex and hippocampal volume with fMRI activation during episodic memory function in elderly controls with no cognitive impairment and individuals with amnesic mild cognitive impairment (aMCI). Both groups displayed limited evidence for a relationship between hippocampal volume and fMRI activation. Smaller right entorhinal cortex volume was correlated with reduced activation in left and right medial frontal cortex (BA 8) during incidental encoding for both aMCI and elderly controls. However, during recognition, smaller left entorhinal cortex volume correlated with reduced activation in right BA 8 for the control group, but greater activation for the aMCI group. There was no significant relationship between entorhinal cortex volume and activation during intentional encoding in either group. The recognition-related dissociation in structure/function relationships in aMCI paralleled our behavioral findings, where individuals with aMCI displayed poorer performance relative to controls during recognition, but not encoding. Taken together, these results suggest that the relationship between entorhinal cortex volume and fMRI activation during episodic memory function is altered in individuals with aMCI.Illinois. Department of Public HealthNational Institute on Aging (Grant P01 AG09466)National Institute on Aging (Grant P30 AG10161)National Institute on Aging (Grant R01 AG017917)National Institute on Aging (Grant T32 AG000257

Regulation of Axonal HCN1 Trafficking in Perforant Path Involves Expression of Specific TRIP8b Isoforms

The functions of HCN channels in neurons depend critically on their subcellular localization, requiring fine-tuned machinery that regulates subcellular channel trafficking. Here we provide evidence that regulatory mechanisms governing axonal HCN channel trafficking involve association of the channels with specific isoforms of the auxiliary subunit TRIP8b. In the medial perforant path, which normally contains HCN1 channels in axon terminals in immature but not in adult rodents, we found axonal HCN1 significantly increased in adult mice lacking TRIP8b (TRIP8b−/−). Interestingly, adult mice harboring a mutation that results in expression of only the two most abundant TRIP8b isoforms (TRIP8b[1b/2]−/−) exhibited an HCN1 expression pattern similar to wildtype mice, suggesting that presence of one or both of these isoforms (TRIP8b(1a), TRIP8b(1a-4)) prevents HCN1 from being transported to medial perforant path axons in adult mice. Concordantly, expression analyses demonstrated a strong increase of expression of both TRIP8b isoforms in rat entorhinal cortex with age. However, when overexpressed in cultured entorhinal neurons of rats, TRIP8b(1a), but not TRIP8b(1a-4), altered substantially the subcellular distribution of HCN1 by promoting somatodendritic and reducing axonal expression of the channels. Taken together, we conclude that TRIP8b isoforms are important regulators of HCN1 trafficking in entorhinal neurons and that the alternatively-spliced isoform TRIP8b(1a) could be responsible for the age-dependent redistribution of HCN channels out of perforant path axon terminals

Disconnection of hippocampal networks contributes to memory dysfunction in individuals with temporal lobe epilepsy

A deficit in declarative memory function is common among individuals with temporal lobe epilepsy. The purpose of this study is to evaluate the relationship between the volume of the hippocampus, entorhinal cortex along with the surrounding parahippocampal white matter and memory performance in those with temporal lobe epilepsy. T1 weighted MRI scans were acquired using a 3-D pulse sequence in 50 individuals with temporal lobe epilepsy. Hippocampal and entorhinal cortex volumes were derived by manually tracing consecutive coronal slices aligned perpendicular to the long axis of the hippocampus. In addition, parahippocampal white matter volumes were determined using voxel based morphometry. Finally, declarative memory was assessed using immediate and delayed verbal and visual memory tests from the Wechsler Memory Scale third edition. Significant correlations were seen between right and left hippocampal volumes and delayed verbal memory test scores. In addition, left parahippocampal white matter showed positive correlations with immediate and delayed verbal and visual recall. Furthermore, regression models found that the right hippocampus and left parahippocampal white matter were the best predictors of immediate and delayed verbal and visual memory performance. These results show that a decrease in white matter fibers projecting to the hippocampus may cause a disruption of incoming multi-modal sensory information, contributing to the memory decline seen in individuals with temporal lobe epilepsy

Magnetoencephalography and New Imaging Modalities in Epilepsy

The success of epilepsy surgery is highly dependent on correctly identifying the entire epileptogenic region. Current state-of-the-art for localizing the extent of surgically amenable areas involves combining high resolution three-dimensional magnetic resonance imaging (MRI) with electroencephalography (EEG) and magnetoencephalography (MEG) source modeling of interictal epileptiform activity. Coupling these techniques with newer quantitative structural MRI techniques, such as cortical thickness measurements, however, may improve the extent to which the abnormal epileptogenic region can be visualized. In this review we assess the utility of EEG, MEG and quantitative structural MRI methods for the evaluation of patients with epilepsy and introduce a novel method for the co-localization of a structural MRI measurement to MEG and EEG source modeling. When combined, these techniques may better identify the extent of abnormal structural and functional areas in patients with medically intractable epilepsy

Ultrastructural localization of HCN1 in middle molecular layer (MML) of dentate gyrus.

<p>a) Light micrographs of silver-intensified immunogold-stained hippocampal slices show the presence of a thin band of HCN1 immunoreactivity in MML in the TRIP8b^−/− (arrows), but not in the wildtype mice. Note also the lack of HCN1 enrichment in stratum lacunosum-moleculare (SLM, asterisks) of CA1 in the TRIP8b^−/−-section, as described by Lewis et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032181#pone.0032181-Lewis2" target="_blank">[12]</a> (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032181#pone-0032181-g001" target="_blank">Fig. 1d–f</a>). b, c) Electron micrographs of serial sections showing immunopositive axonal boutons in a TRIP8b^−/− mouse, making both perforated (arrow) and nonperforated synapses with dendritic spines in MML. Abbreviations: at, axon terminal; sp, spine. d) Percentage of axonal boutons, immunopositive for HCN1, making axospinous synapses in MML in wildtype (black) and TRIP8b^−/− mice (white). e) Average number of particles per synaptic bouton in wildtype (black) and TRIP8b^−/− mice (white). Data were obtained from two mice of each genotype, and based on analyses of 25 synaptic boutons from each mouse (100 axonal boutons total) from the MML. Serial ultrathin sections were obtained from slices similar to those shown in (a).</p

Differential effects of TRIP8b isoforms on localization of HCN1 in the middle molecular layer (MML) of dentate gyrus.

<p>a–c) Representative low power images of coronal sections of adult wildtype mouse brain show the characteristic distribution of TRIP8b (a) and HCN1 (b) immunoreactivity in hippocampus, with HCN1 and TRIP8b staining most intense in stratum lacunosum-moleculare (SLM) of CA1, and low expression in stratum pyramidale (SP), stratum oriens (SO) and stratum radiatum (SR). In contrast, much lower levels of HCN1 and TRIP8b are expressed in hippocampal dentate gyrus (DG). d–f) Interestingly, in adult TRIP8b^−/− mice the immunoreactivity of HCN1 is increased in the MML of DG (arrows in e), where the granule cells are innervated by axons from medial EC via the perforant path. No changes in HCN1 expression were observed in mossy fibres (empty circles), whereas there is significant reduction of HCN1 staining in the SLM of CA1 (asterisks). g–i) Adult TRIP8b[1b/2]^−/− mice expressing TRIP8b isoforms 1a and 1a-4 show similar HCN1 staining patterns to wildtype mice in all hippocampal subregions. Scale bar: 200 µm. j–l) Higher magnification views of HCN1 immunoreactivity in TRIP8b^−/− DG clearly show the increased HCN1 staining in MML (k) as compared with wildtype (j) and TRIP8b[1b/2]^−/− mice (l). Scale bar: 50 µm. m–n) HCN1 immunofluorescence was measured as a function of distance across the superior blade of the dentate gyrus as indicated in the diagram (m), and demonstrates higher HCN1 expression in MML in TRIP8b^−/− (red circles) as compared to wildtype (black circles) and TRIP8b[1b/2]^−/− (blue circles) mice (n). OML - outer molecular layer, MML - middle molecular layer, IML - inner molecular layer, GCL - granule cell layer, Hil - hilus. Asterisks in (n) denote statistical significance (*p<0.05, **p<0.01, ***p<0.001).</p

Expression of HCN1-EGFP and TRIP8b isoforms after single-transfection in immature entorhinal neuron cultures.

<p>Confocal images showing representative neurons in “immature cultures” (P0+4 days <i>in vitro</i>) single-transfected with either HCN1-EGFP (a–c), TRIP8b(1a-4) (d-f) or TRIP8b(1a) (g–i). For the identification of axons, the microtubule-associated protein Tau-1 was co-labeled (b, e, h). Note: Single-transfection resulted in a relatively homogeneous distribution of the overexpressed proteins within neuronal compartments, including the axon (arrows). Scale bar: 20 µm.</p