Jan C. Frankowski
Hunt Lab
4/26/2018

Interneuron function
• Morphologically and functionally heterogeneous population of neurons that make up approximately 20% of all neurons in the neocortex and hippocampus
• Release gamma-aminobutyric acid
(GABA), hyperpolarizing the membrane potential.
• Integration of excitatory inputs to principle neurons
• Cellular output and action potential generation
• Rhythmic network oscillations
Wonders and Anderson, 2006

What does the hippocampus do?
• Learning
• Memory
• Attention
• Episodic memory retrieval

Anatomy of the hippocampus

Interneuron subtypes are spatially segregated and functionally distinct
PV SST Reelin nNOS CR

Traumatic brain injury
• External mechanical force damages the brain (e.g., from a bump, blow, or jolt to the head)
• Traumatic brain injury (TBI) afflicts nearly 6 million Americans
• Substantially increases the risk for a variety of physical, cognitive, emotional, social and psychiatric health problems, and it is one of the most common causes of drug-resistant epilepsy in humans
• There are no effective therapies for brain trauma

Why study interneurons in the hippocampus after
TBI?
• In a study of 112 fatal human head injuries, damage to the hippocampus was noted in 94 cases (84%)
• TBI is one of the greatest risk factors for adult onset TLE
• Human cortical tissue shows loss of interneurons after TBI
• Human hippocampus shows hilar interneuron loss
• TBI shares common features with other diseases with interneuron dysfunction
• However, we currently do not know how interneurons in the hippocampus respond to TBI injury
Kotapka, Acta. Neuropathologica, 1992

Controlled cortical impact brain injury model
- High degree of control over injury parameters
- Precise and reproducible
- Injury severity can be graded
- Scalable to larger animals
Frankowski and Hunt, Kopf Carrier 2018

Experimental design
• P60 GAD67-GFP mice subjected to craniotomy alone, 0.5mm
CCI or 1mm CCI
• 30d later sacrificed, perfused, cut 300um series of coronal sections
• GFP+ cell density was quantified bilaterally in 5 serial sections of the dorsal hippocampus in DG, CA1, CA3
• Layer analysis done on 3 serial sections unilaterally in DG and CA1
• PV+, SST+, CR+, nNOS+, Reelin+ cell density was quantified in
3 serial sections of the dorsal hippocampus in DG, CA1, CA3
• Layer analysis done on 3 serial sections unilaterally in DG and CA1

CCI produces graded contusive injury

Hippocampal interneuron loss in DG, CA3 and CA1

Layer-specific loss of hippocampal interneurons
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Interneuron subtype-specific loss in DG, CA3 and CA1

Layer-specific loss of interneuron subtypes

• Cell loss is a function of laminar position and injury severity rather than neurochemical identity
• The hilus is most vulnerable, while the molecular layer is preserved
• Feedback inhibition is compromised after TBI, which may lead to a hyper-excitable hippocampus