In:
Epilepsia, Wiley, Vol. 54, No. 10 ( 2013-10), p. 1834-1844
Abstract:
The chemokine fractalkine/ CX 3 CL 1 and its receptor CX 3 CR 1 are widely expressed in the central nervous system ( CNS ). Recent evidence showed that CX 3 CL 1 participates in inflammatory responses that are common features of CNS disorders, such as epilepsy. Mesial temporal lobe epilepsy ( MTLE ) is the prevalent form of focal epilepsy in adults, and hippocampal sclerosis ( HS ) represents the most common underlying pathologic abnormality, as demonstrated at autopsy and postresection studies. Relevant features of MTLE are a characteristic pattern of neuronal loss, as are astrogliosis and microglia activation. Several factors affect epileptogenesis in patients with MTLE , including a lack of γ‐aminobutyric acid ( GABA )ergic inhibitory efficacy. Therefore, experiments were designed to investigate whether, in MTLE brain tissues, CX 3 CL 1 may influence GABA A receptor ( GABA A R ) mediatedtransmission, with a particular focus on the action of CX 3 CL 1 on the use‐dependent decrease (rundown) of the GABA ‐evoked currents ( I GABA ), a feature underlying the reduction of GABA ergic function in epileptic tissue. Methods Patch‐clamp recordings were obtained from cortical pyramidal neurons in slices from six MTLE patients after surgery. Alternatively, the cell membranes from epileptic brain tissues of 17 MTLE patients or from surgical samples and autopsies of nonepileptic patients were microtransplanted into Xenopus oocytes, and I GABA were recorded using the standard two‐microelectrode voltage‐clamp technique. Immunohistochemical staining and double‐labeling studies were carried out on the same brain tissues to analyze CX 3 CR 1 expression. Key Findings In native pyramidal neurons from cortical slices of patients with MTLE , CX 3 CL 1 reduced I GABA rundown and affected the recovery of I GABA amplitude from rundown. These same effects were confirmed in oocytes injected with cortical and hippocampal MTLE membranes, whereas CX 3 CL 1 did not influence I GABA in oocytes injected with nonepileptic tissues. Consistent with a specific effect of CX 3 CL 1 on tissues from patients with MTLE , CX 3 CR 1 immunoreactivity was higher in MTLE sclerotic hippocampi than in control tissues, with a prominent expression in activated microglial cells. Significance These findings indicate a role for CX 3 CL 1 in MTLE , supporting recent evidence on the relevance of brain inflammation in human epilepsies. Our data demonstrate that in MTLE tissues the reduced GABA ergic function can be modulated by CX 3 CL 1. The increased CX 3 CR 1 expression in microglia and the modulation by CX 3 CL 1 of GABA ergic currents in human epileptic brain suggests new therapeutic approaches for drug‐resistant epilepsies based on the evidence that the propagation of seizures can be influenced by inflammatory processes.
Type of Medium:
Online Resource
ISSN:
0013-9580
,
1528-1167
DOI:
10.1111/epi.2013.54.issue-10
Language:
English
Publisher:
Wiley
Publication Date:
2013
detail.hit.zdb_id:
2002194-X
