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Traumatic brain injury in mice deficient in Bid: effects on histopathology and functional outcome
Daniela Bermpohl1, Zerong You, Stanley J Korsmeyer
1Neuroscience Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Abstract:
Bid is a proapoptotic member of the Bcl-2 family that mediates cell death by caspase-dependent and -independent pathways. We tested mice genetically deficient in Bid in a controlled cortical impact (CCI) model to examine the hypothesis that Bid contributes to cell death and functional outcome after traumatic brain injury. After CCI, truncated Bid (15 kDa) was robustly detected in cortical brain homogenates of wild-type mice. Bid-/- mice had decreased numbers of cortical cells with acute plasmalemma injury at 6 h (wild type (WT), 1721+/-124; Bid-/-, 1173+/-129 cells/ x 200 field; P<0.01), decreased numbers of cells expressing cleaved caspase-3 in the dentate gyrus at 48 h (WT, 113+/-15; Bid-/-, 65+/-9 cells/ x 200 field; P<0.05), and reduced lesion volume at 12 days (Bid-/-, 5.9+/-0.4 mm(3); WT, 8.4+/-0.4 mm(3); P<0.001), but did not differ from WT mice at later times after injury regarding lesion size (30 days) or brain tissue atrophy (40 days). Compared with naïve mice, injured mice in both groups performed significantly worse on motor and Morris water maze (MWM) tests; however, mice deficient in Bid did not differ from WT in postinjury motor and MWM performance. The data show that Bid deficiency decreases early posttraumatic brain cell death and tissue damage, but does not reduce functional outcome deficits after CCI in mice.
Insights
Bid deficiency reduces early cell death and tissue damage after traumatic brain injury (TBI) in mice. However, it does not improve long-term functional outcomes following the injury.
Area of Science:
- Neuroscience
- Cell Biology
- Trauma Research
Background:
- Bid is a proapoptotic protein in the Bcl-2 family.
- Bid mediates cell death through caspase-dependent and -independent pathways.
- Traumatic brain injury (TBI) involves significant cell death and functional deficits.
Purpose of the Study:
- To investigate the role of Bid in TBI pathogenesis.
- To test the hypothesis that Bid contributes to cell death and functional outcome after TBI.
- To examine Bid's involvement in a controlled cortical impact (CCI) model of TBI.
Main Methods:
- Utilized a controlled cortical impact (CCI) model in mice genetically deficient in Bid (Bid-/-) and wild-type (WT) littermates.
- Assessed acute plasmalemma injury, cleaved caspase-3 expression, and lesion volume at various time points post-TBI.
- Evaluated motor function and spatial learning/memory using motor tests and the Morris water maze (MWM).
Main Results:
- Bid-/- mice showed decreased acute cortical cell injury and reduced cleaved caspase-3 expression in the dentate gyrus post-CCI compared to WT mice.
- A significant reduction in lesion volume was observed in Bid-/- mice at 12 days post-injury.
- Despite reduced early damage, Bid-/- mice did not exhibit improved motor or MWM performance compared to WT mice at later time points.
Conclusions:
- Bid deficiency mitigates early post-TBI cell death and acute tissue damage.
- Bid does not appear to influence long-term functional recovery or brain tissue atrophy after TBI.
- Targeting Bid may offer a strategy to reduce initial injury severity but may not be sufficient for complete functional recovery.
