Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction

Abstract

Epilepsy is a prevalent neurological disorder associated with significant morbidity and mortality, but the only available drug therapies target its symptoms rather than the underlying cause. The process that links brain injury or other predisposing factors to the subsequent emergence of epilepsy is termed epileptogenesis. Substantial research has focused on elucidating the mechanisms of epileptogenesis so as to identify more specific targets for intervention, with the hope of preventing epilepsy before seizures emerge. Recent work has yielded important conceptual advances in this field. We suggest that such insights into the mechanisms of epileptogenesis converge at the level of cortical circuit dysfunction.

Figure 1. Mechanistic roles of the mTOR pathway and REST in epileptogenesis

a | A simplified version of the mammalian target of rapamycin (mTOR) pathway, highlighting epilepsy-related molecules. For a more complete illustration of the mTOR pathway, see REF. . b | A schematic depicting repressor element 1 (RE1)-silencing transcription factor (REST)-mediated gene silencing triggered by status epilepticus. REST co-repressor 1 (CoREST), a component of the histone deacetylase (HDAC) complex, interacts with REST to mediate transcriptional repression. The asterisk indicates genes for which there is specific experimental evidence suggesting regulation by REST or HDAC inhibiton after status epilepticus^,. AMPK, AMP-activated protein kinase; BDNF, brain-derived neurotrophic factor; GABRB3; type A GABA receptor β3 subunit; GABRD; type A GABA receptor δ-subunit; GRIA2, ionotropic AMPA 2 glutamate receptor; HCN1, hyperpolarization-activated cyclic nucleotide-gated channel subunit 1; IRS1, insulin receptor substrate 1; KCC2; potassium/chloride co-transporter 2; KCNC, potassium voltage-gated channel subfamily C; LKB1, liver kinase B1 (also known as serine/threonine kinase STK11); mTORC1, mTOR complex 1; PDK1, 3-phosphoinositide-dependent kinase 1; PI3K, phosphoinositide 3-kinase; PtdIns(4,5)P₂, phosphatidylinositol-4,5-biphosphate; PtdIns(3,4,5)P₃, phosphatidylinositol-3,4,5-triphosphate; PTEN, phosphatase and tensin homologue; RHEB, RAS homologue enriched in brain; STRADA, STE20-related adaptor protein-α; TSC, tuberous sclerosis complex. Part a is modified, with permission, from REF. © (2011) Elsevier.

Figure 2. Embedded loop structures of the temporal lobe

a | The hippocampus receives two inputs, the perforant path (PP) and the temporoammonic (TA) pathway. The entorhinal cortex (EC) is in turn the target of hippocampal output, creating multiple excitatory loops. There is a long loop that originates from the EC and projects to the dentate gyrus (DG) via the PP, from the DG to area CA3 via mossy fibres (MFs), from area CA3 to area CA1 and from area CA1 back to the subiculum (not shown) and/or EC. An intermediate-length loop originates from the EC and projects to area CA3 (via the PP pathway), then to area CA1 and from there to the subiculum and/or EC. A short loop projects from the EC to area CA1 (via the TA pathway) and back to the subiculum and/or EC. Recurrent collaterals (RCs) between CA3 pyramidal cells (PCs) are also shown. b | Simplified connectivity within the DG. Many connections and various inhibitory interneuron subtypes are omitted for clarity^,,. PCs and stellate cells within layer 2 of the medial EC (MEC) and lateral EC (LEC) form the PP to the middle and outer molecular layer, respectively, of the hippocampal DG, as well as to the distal dendrites of PCs in area CA3 (not shown). In the dentate, lateral PP (LPP) and medial PP (MPP) axons synapse onto dentate granule cells (GCs) and onto GABAergic interneurons (including parvalbumin-positive (PV⁺) basket cells and somatostatin-positive (SOM⁺) hilar PP-associated (HiPP) cells) as well as mossy cells in the dentate hilus. c | Selected connections of the TA pathway, which proceeds from layer 3 EC pyramidal and spiny stellate neurons (not shown) to the distal dendrites and distal apical tuft dendrites of CA1 neurons in stratum lacunosum-moleculare (SLM) in the short loop mentioned above as well as to the distal dendrites of CA2 (the intermediate-length loop, not shown). Extrinsic excitatory connections are shown in green; excitatory cells and intrinsic excitatory connections are shown in blue; and inhibitory cells and intrinsic inhibitory connections are shown in red and purple. Bi, bistratified cell; O-LM, oriens lacunosum-moleculare. SC, Schaffer collateral; SO, stratum oriens; SR, stratum radiatum.

Figure 3. Temporal lobe circuit elements under normal conditions

A | Dentate gating in the hippocampus under normal conditions (parts Aa–Ac) and after blockade of GABAergic inhibition (parts Ad–Af). Aa | A voltage-sensitive dye (VSD) image of depolarization that is restricted to the dentate gyrus granule cell layer in response to stimulation of the perforant path in an acute brain slice from the rat hippocampus. Ab | The VSD response is quantified in the dentate gyrus, hilus and area CA3. Ac | The top panel shows a current-clamp recording from a dentate gyrus granule cell and the botttom panel shows the field potential in the dentate gyrus. Ad | The collapse of the dentate after blockade of GABAergic inhibition using 5 μM picrotoxin (PTX; a non-competitive type A (GABA_A) receptor antagonist) is illustrated using VSD imaging. Ae | The quantification of the VSD response shows collapse of the dentate gate, with activation of upstream area CA3 after GABAergic blockade. Af | Blockade of inhibition elicits hyperactivation of dentate granule cells in response to perforant path activation, as shown by the current-clamp recording (top panel) and the field potential (bottom panel). B | Temporoammonic (TA) pathway function in area CA1 under normal conditions (parts Ba, Bb) and following GABAergic blockade (parts Bc, Bd). Ba | Activation within area CA1 in response to stimulation of the TA pathway is spatially restricted to the distal dendrites of CA1 pyramidal cells (indicated by the arrows), which is shown using VSD imaging. Bb | The top panel shows a current-clamp recording from a CA1 pyramidal cell dendrite in response to TA pathway activation, and the bottom panel shows the quantification of the VSD response in stratum oriens (SO), stratum radiatum (SR) and stratum lacunosum-moleculare (SLM) 30 ms after extracellular stimulation of the TA pathway, with evoked excitatory responses (indicated by the asterisk) in SLM. Bc | A VSD image shows that GABAergic feedforward inhibition after application of the GABA_A antagonist gabazine (1 μm) and the GABA_B antagonist CGP 55845A (2 μm) spatially restricts TA pathway activation to the distal dendrites of CA1 pyramidal cells, with loss of spatial segregation within area CA1. Bd | The top panel shows a current-clamp recording from a CA1 pyramidal cell dendrite, and the the bottom panel shows the quantification of the VSD response, with propagation of the response to SR and SO. F, fluorescence; nACSF, normal artificial cerebrospinal fluid. Part A is reproduced, with permission, from REF. © (2007) Elsevier. Part B is reproduced, with permission, from REF. © (2005) Society for Neuroscience.

Figure 4. Circuit dysfunction in temporal lobe epilepsy

a | Dentate gating is impaired during the latent period (1 week after status epilepticus) in an animal model of chronic temporal lobe epilepsy (TLE). The top panel shows voltage-sensitive dye (VSD) recordings of perforant path stimulation under control conditions 5 ms after stimulation (left), at peak (middle) and later (200 ms; right). The top right panel shows restriction of the perforant path-evoked depolarization to the molecular layer of the dentate gyrus (DG). Note that there is minimal area CA3 activation. During the latent period (bottom panel), identical stimulation reveals a delayed peak response as well as >200% increase in activation (as measured by areal pixel activation) in area CA3. b | Gating function is retained in the chronic phase of acquired TLE in the rodent model. The two panels show VSD images of the DG 5 ms (left), 25 ms (middle) and 200 ms (right) after stimulation of the perforant path in control rats (top panel) and in chronically epileptic rats (bottom panel). Under both conditions, there is a strong response in the DG that fails to propagate to area CA3. c | Temporoammonic (TA) pathway dysfunction in the chronic phase of acquired TLE. VSD imaging of TA pathway function in control animals (top panel) and epileptic animals (bottom panel) at 5 ms, 25 ms, 55 ms, 85 ms and 180 ms after stimulation of the TA pathway, producing spatially restricted activity in control animals that aberrantly propagates to the strata radiatum and pyramidale in the epileptic condition. Hil, hilus; F, fluorescence. Part a is reproduced, with permission, from REF. © (2007) Society for Neuroscience. Parts b and c are reproduced, with permission, from REF. © (2006) Society for Neuroscience.