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

Abstract

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, 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 hours post-SE), sub-acutely (1 week post-SE), and during the chronic period (2 months post-SE). Aggrecan expressing PNs decreased by one 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 extracellular matrix. 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.

Age-Related Deterioration of Perineuronal Nets in the Primary Auditory Cortex of Mice

“…Such reduced inhibition with age may be one of the steps in causing an increase in cortical gain and potentially, pathological activity (e.g., tinnitus). Evidence for such pathological activity correlated with changes in PNN comes from studies of epileptogenesis and schizophrenia (Dityatev et al, 2007; McRae et al, 2012). …”

Brain extracellular space, hyaluronan, and the prevention of epileptic seizures

“…Data indicate that the initial decrease in high-molecular-weight HA may be due either to an increase in HA breakdown or a decrease in HA synthesis, or both. For example, it has been shown that status epilepticus in rats causes a decrease in high-molecular-weight HA and a decrease in HAS3 (McRae et al, 2012). Ischemic stroke in humans or middle cerebral artery occlusion in rats is associated with elevated hyaluronidase activity and increases in HA breakdown products (Al’Qteishat et al, 2006a, 2006b).…”

The perineuronal net component of the extracellular matrix in plasticity and epilepsy

“…While all CSPGs family members can be found in PNs, aggrecan is unique because, unlike the other CSPGs and lecticans, in the CNS it is found exclusively in the PNs (Matthews et al, 2002; Galtrey et al, 2008; Morawski et al, 2012). Aggrecan expressing PNs develop postnatally in the hippocampus primarily around PV interneurons (McRae et al, 2010, 2012). Inducing SE with kainic acid early in development, prior to the expression of the PN led to accelerated expression of aggrecan positive PNs.…”

“…SE induced in the adult, after the PN has matured, resulted in a persistent decrease in aggrecan containing PNs at one week persisting up to two months after SE (McRae et al, 2012). Similar to Okamoto’s work there was no decrease in PV expression, in fact there was an increase at one week.…”