Faculty Bibliography

In vivo quantitative magnetic resonance imaging (MRI) was employed to detect brain pathology and map its distribution within control, disomic mice (2N) and in Ts65Dn and Ts1Cje trisomy mice with features of human Down syndrome (DS). In Ts65Dn, but not Ts1Cje mice, transverse proton spin-spin (T(2)) relaxation time was selectively reduced in the medial septal nucleus (MSN) and in brain regions that receive cholinergic innervation from the MSN, including the hippocampus, cingulate cortex, and retrosplenial cortex. Basal forebrain cholinergic neurons (BFCNs) in the MSN, identified by choline acetyltransferase (ChAT) and nerve growth factor receptors p75(NTR) and TrkA immunolabeling were reduced in Ts65Dn brains and in situ acetylcholinesterase (AChE) activity was depleted distally along projecting cholinergic fibers, and selectively on pre- and postsynaptic profiles in these target areas. T(2) effects were negligible in Ts1Cje mice that are diploid for App and lack BFCN neuropathology, consistent with the suspected relationship of this pathology to increased App dosage. These results establish the utility of quantitative MRI in vivo for identifying Alzheimer's disease-relevant cholinergic changes in animal models of DS and characterizing the selective vulnerability of cholinergic neuron subpopulations

Epilepsy in women is influenced by endocrine status and antiepileptic drugs (AEDs), but without an animal model, the effects of endocrine variables and AEDs cannot be easily dissociated from the influence of epilepsy itself. Animal models have had limited utility because experimentally-induced seizures typically result in reproductive failure. This study was conducted to develop an improved animal model. The muscarinic convulsant pilocarpine was used to elicit status epilepticus (SE) in adult female Sprague-Dawley rats. The selective estrogen receptor modulator raloxifene was administered 30 min before pilocarpine. An anticonvulsant barbiturate, pentobarbital, was injected 5-10 min after the onset of SE, and at least once thereafter to minimize acute convulsions. Mortality, morbidity, estrous cyclicity, and the ultimate success of the procedure (i.e. induction of recurrent, spontaneous seizures) were monitored. The combination of raloxifene and pentobarbital led to significantly improved estrous cyclicity compared to previous methods. Animals treated with raloxifene and pentobarbital became epileptic, as defined by the recurrence of spontaneous convulsions in the weeks after SE. The results of this study provide an improved animal model to examine the interactions between seizures and ovarian hormone secretion. The results also suggest that treatment of SE with raloxifene may benefit women with SE

After it was first identified that seizures increase neurogenesis in the adult brain of laboratory animals, the idea that postnatal neurogenesis may be involved in epilepsy became a topic of widespread interest. Since that time, two perspectives have developed. They primarily address temporal lobe epilepsy (TLE), because the data have either been based on animal models of TLE or patients with intractable TLE. The first perspective is that postnatal neurogenesis contributes to the predisposition for seizures in TLE. This premise is founded in the observations showing that there is a dramatic rise in neurogenesis after many types of insults or injuries which ultimately lead to TLE. As a result of the increase in neurogenesis, several changes in the dentate gyrus occur, and the net effect appears to be an increase in excitability. One of the changes is the formation of a population of granule cells (GCs) that mismigrate, leading to ectopic granule cells in the hilus (hilar EGCs) that exhibit periodic bursts of action potentials, and contribute to recurrent excitatory circuitry. Atypical dendrites also form on a subset of GCs, and project into the hilus (hilar basal dendrites). Hilar basal dendrites appear to preferentially increase the glutamatergic input relative to GABAergic synapses, increasing excitability of the subset of GCs that form hilar basal dendrites. The alternate view is that postnatal neurogenesis is a homeostatic mechanism in epilepsy that maintains normal excitability. This idea is supported by studies showing that some of the new GCs that are born after seizures, and migrate into the correct location, have normal or reduced excitability. Here we suggest that both perspectives may be important when considering a therapeutic strategy. It would seem advantageous to limit the numbers of mismigrating GCs and hilar basal dendrites, but maintain normal neurogenesis because it is potentially homeostatic. Maintaining normal neurogenesis is also important because it has been suggested that a decrease in dentate gyrus neurogenesis contributes to depression. It is challenging to design a strategy that would achieve these goals, and it is also difficult to propose how one could administer such a therapy prophylactically, that is, as an 'antiepileptogenic' approach. Another issue to address is how a therapeutic intervention with these goals could be successful if it were administered after chronic seizures develop, when most patients seek therapy. Although difficult, a number of approaches are possible, and technical advances suggest that there are more on the horizon

Downregulation of brain-derived neurotrophic factor (BDNF) in the cortex occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival, synaptic plasticity, and memory, BDNF reduction may contribute to synaptic and cellular loss and memory deficits characteristic of AD. In vitro evidence suggests that amyloid-beta (A beta) contributes to BDNF downregulation in AD, but the specific A beta aggregation state responsible for this downregulation in vivo is unknown. In the present study, we examined cortical levels of BDNF mRNA in three different transgenic AD mouse models harboring mutations in APP resulting in A beta overproduction, and in a genetic mouse model of Down syndrome. Two of the three A beta transgenic strains (APP(NLh) and TgCRND8) exhibited significantly decreased cortical BDNF mRNA levels compared with wild-type mice, whereas neither the other strain (APP(swe)/PS-1) nor the Down syndrome mouse model (Ts65Dn) was affected. Only APP(NLh) and TgCRND8 mice expressed high A beta(42)/A beta(40) ratios and larger SDS-stable A beta oligomers (approximately 115 kDa). TgCRND8 mice exhibited downregulation of BDNF transcripts III and IV; transcript IV is also downregulated in AD. Furthermore, in all transgenic mouse strains, there was a correlation between levels of large oligomers, A beta(42)/A beta(40), and severity of BDNF decrease. These data show that the amount and species of A beta vary among transgenic mouse models of AD and are negatively correlated with BDNF levels. These findings also suggest that the effect of A beta on decreased BDNF expression is specific to the aggregation state of A beta and is dependent on large oligomers

It has been well documented that alpha-calcium/calmodulin-dependent protein kinase II (alphaCaMKII) is central to synaptic plasticity such as long-term potentiation, an activity-dependent strengthening of synapses that is thought to underlie certain types of learning and memory. However, the mechanisms by which alphaCaMKII may regulate neuronal excitability remain unclear. Here, we report that alphaCaMKII knock-in mice with a targeted T286A point mutation that prevents its autophosphorylation (alphaCaMKII(T286A)) showed increased excitability of CA1 pyramidal neurons compared with wild-type controls, as measured by a decrease in the slow component of post-burst afterhyperpolarization (sAHP) following high-frequency stimulation of Schaffer collateral afferent fibers. In contrast, AHP was indistinguishable between alphaCaMKII(T286A) and wild-type mice when it was evoked by somatic current injections, indicating that the hyperexcitability is observed specifically in response to synaptic stimulation in this mutant. Taken together, our results suggest that alphaCaMKII functions to downregulate CA1 neuron excitability following synaptic stimulation, presumably supporting the functionally adaptive modulation of excitability during hippocampal learning or providing a negative feedback mechanism that would prevent neurons from becoming hyperexcitable and promote network stability

The prospect of using cell-based interventions (CBIs) to treat neurological conditions raises several important ethical and policy questions. In this target article, we focus on issues related to the unique constellation of traits that characterize CBIs targeted at the central nervous system. In particular, there is at least a theoretical prospect that these cells will alter the recipients' cognition, mood, and behavior-brain functions that are central to our concept of the self. The potential for such changes, although perhaps remote, is cause for concern and careful ethical analysis. Both to enable better informed consent in the future and as an end in itself, we argue that early human trials of CBIs for neurological conditions must monitor subjects for changes in cognition, mood, and behavior; further, we recommend concrete steps for that monitoring. Such steps will help better characterize the potential risks and benefits of CBIs as they are tested and potentially used for treatment.

OBJECTIVE: To examine alpha7 nicotinic acetylcholine receptor (nAChR) binding and beta-amyloid (Abeta) peptide load in superior frontal cortex (SFC) across clinical and neuropathological stages of Alzheimer disease (AD). DESIGN: Quantitative measures of alpha7 nAChR by [(3)H]methyllycaconitine binding and Abeta concentration by enzyme-linked immunosorbent assay in SFC were compared across subjects with antemortem clinical classification of no cognitive impairment, mild cognitive impairment, or mild to moderate AD, and with postmortem neuropathological diagnoses. SETTING: Academic medical center. Subjects Twenty-nine elderly retired clergy. MAIN OUTCOME MEASURES: Quantitative measures of alpha7 nAChR binding and Abeta peptide concentration in SFC. RESULTS: Higher concentrations of total Abeta peptide in SFC were associated with clinical diagnosis of mild to moderate AD (P = .02), lower Mini-Mental State Examination scores (P = .003), presence of cortical Abeta plaques (P = .02), and likelihood of AD diagnosis by the National Institute on Aging-Reagan criteria (P = .002). Increased alpha7 nAChR binding was associated with National Institute on Aging-Reagan diagnosis (P = .02) and, albeit weakly, the presence of cortical Abeta plaques (P = .08). There was no correlation between the 2 biochemical measures. CONCLUSIONS: These observations suggest that during the clinical progression from normal cognition to neurodegenerative disease state, total Abeta peptide concentration increases while alpha7 nAChRs remain relatively stable in SFC. Regardless of subjects' clinical status, however, elevated alpha7 nAChR binding is associated with increased Abeta plaque pathology, supporting the hypothesis that cellular expression of these receptors may be upregulated selectively in Abeta plaque-burdened brain areas.

The endocannabinoid system, including endogenous ligands ('endocannabinoids' ECs), their receptors, synthesizing and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. ECs are bioactive lipids, which comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the best studied ECs, and act as agonists of cannabinoid receptors. Thus, AEA and 2-AG mimic several pharmacological effects of the exogenous cannabinoid delta9-tetrahydrocannabinol (Delta(9)-THC), the psychoactive principle of cannabis sativa preparations like hashish and marijuana. Recently, however, several lines of evidence have suggested that the EC system may play an important role in early neuronal development as well as a widespread role in neurodegeneration disorders. Many of the effects of cannabinoids and ECs are mediated by two G protein-coupled receptors (GPCRs), CB1 and CB2, although additional receptors may be implicated. Both CB1 and CB2 couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. This new system is briefly presented in this review, in order to put in a better perspective the role of the EC pathway from neurodevelopment to neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In addition, the potential exploitation of antagonists of CB1 receptors, or of inhibitors of EC metabolism, as next-generation therapeutics is discussed