Migraine mutations impair hippocampal learning despite enhanced long-term potentiation.

To explain cognitive and memory difficulties observed in some familial hemiplegic migraine (FHM) patients, we examined hippocampal neurotransmission and plasticity in knock-in mice expressing the FHM type 1 (FHM1) R192Q gain-of function mutation in the CACNA1A gene that encodes the α1A subunit of neuronal CaV2.1 channels. We determined stimulus intensity-response curves for anterior commissure-evoked hippocampal CA1 field potentials in strata pyramidale and radiatum and assessed neuroplasticity by inducing long-term potentiation (LTP) and long-term depression (LTD) in anesthetized mice in vivo. We also studied learning and memory using contextual fear-conditioning, Morris water maze, and novel object recognition tests. Hippocampal field potentials were significantly enhanced in R192Q mice compared with wild-type controls. Stimulus intensity-response curves were shifted to the left and displayed larger maxima in the mutants. LTP was augmented by twofold in R192Q mice, whereas LTD was unchanged compared with wild-type mice. R192Q mice showed significant spatial memory deficits in contextual fear-conditioning and Morris water maze tests compared with wild-type controls. Novel object recognition was not impaired in R192Q mice; however, mice carrying the more severe S218L CACNA1A mutation showed marked deficits in this test, suggesting a genotype-phenotype relationship. Thus, whereas FHM1 gain-of-function mutations enhance hippocampal excitatory transmission and LTP, learning and memory are paradoxically impaired, providing a possible explanation for cognitive changes detected in FHM. Data suggest that abnormally enhanced plasticity can be as detrimental to efficient learning as reduced plasticity and highlight how genetically enhanced neuronal excitability may impact cognitive function.

Strain Differences in Presynaptic Function: PROTEOMICS, ULTRASTRUCTURE, AND PHYSIOLOGY OF HIPPOCAMPAL SYNAPSES IN DBA/2J AND C57Bl/6J MICE.

The inbred strains C57BL/6J and DBA/2J (DBA) display striking differences in a number of behavioral tasks depending on hippocampal function, such as contextual memory. Historically, this has been explained through differences in postsynaptic protein expression underlying synaptic transmission and plasticity. We measured the synaptic hippocampal protein content (iTRAQ (Isobaric Tags for Relative and Absolute Quantitation) and mass spectrometry), CA1 synapse ultrastructural morphology, and synaptic functioning in adult C57BL/6J and DBA mice. DBA mice showed a prominent decrease in the Ras-GAP calcium-sensing protein RASAL1. Furthermore, expression of several presynaptic markers involved in exocytosis, such as syntaxin (Stx1b), Ras-related proteins (Rab3a/c), and rabphilin (Rph3a), was reduced. Ultrastructural analysis of CA1 hippocampal synapses showed a significantly lower number of synaptic vesicles and presynaptic cluster size in DBA mice, without changes in postsynaptic density or active zone. In line with this compromised presynaptic morphological and molecular phenotype in DBA mice, we found significantly lower paired-pulse facilitation and enhanced short term depression of glutamatergic synapses, indicating a difference in transmitter release and/or refilling mechanisms. Taken together, our data suggest that in addition to strain-specific postsynaptic differences, the change in dynamic properties of presynaptic transmitter release may underlie compromised synaptic processing related to cognitive functioning in DBA mice.

Clinical outcomes after peripheral blood stem cell donation by related donors: a Dutch single-center cohort study.

BACKGROUND: Relatives donating peripheral blood stem cells (PBSCs) may be accepted for donation on less strict criteria than unrelated donors. We evaluated the occurrence of adverse events during procedure and follow-up, with a special focus on donors who would have been deferred as unrelated donors. STUDY DESIGN AND METHODS: All 268 related PBSC donors at our center (1996-2006) were included. Data were retrospectively collected from medical reports and standard follow-up. Health questionnaires were sent from 2007. Medical outcomes of donors, deferrable or eligible according to international criteria for unrelated donation, were compared. RESULTS: Forty donors (15%) would have been deferred for unrelated donation. Short-term adverse events occurred in 2% of procedures. Questionnaires were returned by 162 (60%) donors on average 7.5 years after donation, bringing total person-years of follow-up to 1278 (177 in deferrable donors). Nine malignancies and 14 cardiovascular events were reported. The incidence rate of cardiovascular events in eligible donors was 6.5 (95% confidence interval [CI], 2.5-12.3) per 1000 person-years compared to 44.9 (95% CI, 17.4-85.2) in deferrable donors; incidence rates of malignancies were 4.6 (1.4-9.6) and 24.0 (6.0-53.9) per 1000 person-years, respectively, in eligible and deferrable donors. All incidence rates were within the range of age- and sex-matched general population. No autoimmune disorders were reported. CONCLUSION: In both the eligible and the deferrable related donors treated with granulocyte-colony-stimulating factor there are few short-term and long-term problems. The occurrence of post-PBSC cardiovascular events and malignant disease in related donors appears to be within the range of the general population.