Biology Reference
In-Depth Information
I
NTRODUCTION
Temporal lobe epilepsy (TLE) is the most frequent type of focal epilepsy in adults [1, 2].
The seizure focus in these patients typically resides in mesial temporal regions of the brain,
such as the hippocampus [3]. The surgically resected hippocampus from TLE patients very
often shows neurodegenerative changes, collectively termed hippocampal sclerosis [3]. In
hippocampal sclerosis, one observes gliosis and a loss of nerve cells [4]. Other changes, at a
functional level, include the hypersynchronization and hyperexcitability of neurons [5, 6]. As
hyperexcitability increases, an increasing number of neurons are recruited into abnormal
discharge patterns, a process that has been referred to as secondary epileptogenesis or
activity-induced epileptogenesis [7, 8].
Interestingly, in addition to neurodegenerative and excitability changes, the hippocampus
from TLE patients shows neuronal reorganization - a form of brain plasticity in response to
seizure activity or injury [7, 9, 10]. Experimentally, the long-term brain plasticity found in
animals subjected to kindling, a widely-used model of epileptogenesis, or to chemically-
induced epilepsy, a common method for inducing epileptic activity, appears to be related to a
long-term potentiation (LTP)-like mediated reorganization of the neural networks [8]. LTP is
a widely accepted model of synaptic plasticity that results in long-term activity-dependent
synaptic change, a mechanism possibly involved in memory encoding [11, 12]. Data suggest
that patterns of circuit reorganization can be induced depending on the location of the initial
seizure activation and focus, which may depend on LTP or LTP-like mechanisms [8].
However, LTP impairments also have been reported following kindling, suggesting a
complex role for LTP in epilepsy [13]. In this chapter, these ideas are discussed along with
current studies that attempt to show potential links between LTP and the up-regulation of
nerve growth factors (and other related molecules) in the contexts of plasticity and epilepsy.
Studies of this kind may set the stage for understanding potential new drug targets for
epileptic patients.
Hippocampal circuitry
There has been much interest in the hippocampal formation since it was recognized many
years ago to play a major role in various forms of memory [14]. Importantly, particular
regions of the hippocampus also have high seizure susceptibility, and have been shown to be
especially vulnerable to the effects of ischemia and head trauma [15]. Additionally, the
hippocampal formation, especially the dentate gyrus, shows some of the most profound types
of structural and functional plasticity in the epileptic brain [7].
Pathways of the hippocampal formation have been characterized, showing that the overall
pattern of connectivity is a trisynaptic circuit possessing primarily (but not exclusively)
unidirectional serial and parallel connections [16]. Inputs to the hippocampus begin with the
perforant path (lateral and medial tracts), which arise in the entorhinal cortex (layer II); the
perforant path terminates in the dentate gyrus and the CA3 subfield of the hippocampus (in
addition, there is an entorhinal cortex projection to CA1 arising from cells in layer III).
Granule cells in the dentate gyrus give rise to mossy fibers that terminate on the dendrites of
CA3 pyramidal cells. CA3 pyramidal cells project primarily to CA1 pyramidal cells along the
