Esther Baranov

Persistent decrease in multiple components of the perineuronal net following status epilepticus

In the rodent model of temporal lobe epilepsy, there is extensive synaptic reorganization within the hippocampus following a single prolonged seizure event, after which animals eventually develop epilepsy. The perineuronal net (PN), a component of the neural extracellular matrix (ECM), primarily surrounds inhibitory interneurons and, under normal conditions, restricts synaptic reorganization. The objective of the current study was to explore the effects of status epilepticus (SE) on PNs in the adult hippocampus. The aggrecan component of the PN was studied, acutely (48 h post‐SE), sub‐acutely (1 week post‐SE) and during the chronic period (2 months post‐SE). Aggrecan expressing PNs decreased by 1 week, likely contributing to a permissive environment for neuronal reorganization, and remained attenuated at 2 months. The SE‐exposed hippocampus showed many PNs with poor structural integrity, a condition rarely seen in controls. Additionally, the decrease in the aggrecan component of the PN was preceded by a decrease in hyaluronan and proteoglycan link protein 1 (HAPLN1) and hyaluronan synthase 3 (HAS3), which are components of the PN known to stabilize the connection between aggrecan and hyaluronan, a major constituent of the ECM. These results were replicated in vitro with the addition of excess KCl to hippocampal cultures. Enhanced neuronal activity caused a decrease in aggrecan, HAPLN1 and HAS3 around hippocampal cells in vivo and in vitro, leaving inhibitory interneurons susceptible to increased synaptic reorganization. These studies are the foundation for future experiments to explore how loss of the PN following SE contributes to the development of epilepsy.

Aggrecan expression, a component of the inhibitory interneuron perineuronal net, is altered following an early-life seizure.

The perineuronal net (PN), a component of the neural extracellular matrix (ECM), is a dynamic structure whose expression decreases following diminished physiological activity. Here, we analyzed the effects of increased neuronal activity on the development of aggrecan, a component of the PN, in the hippocampus. We show aggrecan expression to be prominent around parvalbumin (PV) interneurons in the postnatal hippocampus. Moreover, after seizure induction in early life there was a significant increase in aggrecan expression in a region specific manner during the course of development. We conclude that increased neuronal activity leads to accelerated expression of PNs in the hippocampus that attenuates in the adult hippocampus. This study shows the dynamic nature of the PN component of the ECM and the role neuronal activity has in molding the extracellular milieu of inhibitory interneurons.

Perineuronal net degradation in epilepsy.

We previously reported loss of perineuronal net (PN) immunohistochemical staining around parvalbumin‐positive interneurons in the hippocampus of rats after an episode of status epilepticus (SE). We hypothesized that the loss of the PN could alter seizure susceptibility and that matrix metalloproteinases (MMPs) were candidates for degradation of the PN following SE.

Increased metalloproteinase activity in the hippocampus following status epilepticus

Increased neuronal plasticity and neuronal cell loss has been implicated in the development of epilepsy following injury. Parvalbumin fast spiking inhibitory interneurons have a robust extracellular matrix coating their cell bodies and the proximal dendrites called the perineuronal net (PNN). The role of the PNN is not clear but it has been implicated in closing of the critical period, altering seizure thresholds and providing neuronal protection from oxidative stress. The PNN is susceptible to degradation following a prolonged seizure and there is an increase in proteolytic-fragments of the PNN enriched proteoglycan aggrecan (Dzwonek et al., 2004). Here we demonstrate an increase in matrix metalloproteinase (MMP) activity in the hippocampus following status epilepticus (SE). We further assessed MMP3 and 13, two of 24 identified MMPs, both MMP3 and 13 mRNA increase in the hippocampus after SE and MMP13 activity increases by functional assay as well as it co-localizes with PNN in rat brain. In contrast, two of the brain expressed ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) also implicated in aggrecan degradation, did not consistently increase following SE though ADAMTS4 is highly expressed in glia and ADAMTS5 in neuronal cell bodies and their processes. The increase in MMP activity following SE suggests that in the future studies, MMP inhibitors are candidates for blocking PNN degradation and assessing the role of the PNN loss in epileptogenesis and cellular function.

Health beliefs regarding pediatric cerebral palsy among caregivers in Botswana: A qualitative study

BACKGROUND Cerebral palsy (CP) is the most common motor disability worldwide with an incidence of 2.5 per 1,000 births globally. Health beliefs among caregivers may be major drivers of health-related behaviours and service utilization, but little is known regarding health beliefs around CP in Africa. METHODS Between July 2013 and September 2015, children with CP were identified in Gaborone, Botswana, and their caregivers were invited to participate in a qualitative study utilizing semistructured in-person one-on-one interviews. Interview questions addressed their understanding of CP, challenges of caring for a handicapped child, and community response to children with CP. RESULTS Sixty-two caregivers participated in the study. Common themes elicited were variable knowledge about CP, financial and physical burden, lack of therapies and educational resources, and the impact of stigma. Caregivers in Botswana generally subscribed to a biomedical explanation of CP but expressed concerns regarding more stigmatizing folks beliefs expressed in the community. CONCLUSION Health beliefs regarding CP in Botswana likely have a significant impact on utilization of healthcare resources. Information from this study should inform future educational interventions for caregivers of children with CP.