Karl W. Hasel

Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia

Microglial activation is an early and common feature of almost all neuropathologies, including multiple sclerosis, Alzheimers disease and mechanical injury. To better understand the relative contributions microglia make toward neurodegeneration and neuroprotection, we used TOGA® to identify molecules expressed by microglia and regulated by inflammatory signals. Triggering receptor expressed on myeloid cells‐2 (TREM‐2) was among the mRNAs identified as being expressed by unactivated microglia, but down‐regulated by lipopolysaccharide/interferon γ. In the healthy CNS, not all microglia expressed TREM‐2. Microglial expression of TREM‐2 varied not only between brain regions but also within each brain region. Brain regions with an incomplete blood–brain barrier had the lowest percentages of TREM‐2‐ expressing microglia, whereas the lateral entorhinal and cingulate cortex had the highest percentages. A novel form of TREM‐2b that lacked a transmembrane domain was detected, perhaps indicating a soluble form of the protein. Taken together, these data suggest that (1) subsets of microglia are specialized to respond to defined extracellular signals; and (2) regional variations in TREM‐2 expression may contribute to the varying sensitivities of different brain regions to similar pathological signals.

Clozapine increases apolipoprotein D expression in rodent brain: towards a mechanism for neuroleptic pharmacotherapy

In contrast to typical neuroleptic drugs, which have high affinities for dopamine D2 receptors, clozapine binds to multiple neurotransmitter receptors. The mechanisms responsible for its superior clinical efficacy over typical neuroleptics remain unknown. Using an automated genomics approach, total gene expression analysis (TOGA), we found an approximately threefold increase in the accumulation of the mRNA encoding apolipoprotein D (apoD) in mouse striatum in response to chronic treatment with clozapine. While in control animals, apoD is expressed predominantly in astrocytes, in situ hybridization and immunohistochemical studies indicated a substantial increase in apoD expression in neurons of the striatum, globus pallidus and thalamus after 2 weeks of clozapine treatment. Clozapine‐induced increases in apoD expression were also observed in some white matter regions. These results suggest that apoD is a mediator in the mechanisms of clozapine and thus that deficiencies in aspects of lipid metabolism may be responsible for psychoses.