Activity-dependent neuronal plasticity is a fundamental mechanism through which the nervous system adapts to sensory experience. Several lines of evidence suggest that parvalbumin (PV+) interneurons are essential in this process, but the molecular mechanisms underlying the influence of experience on interneuron plasticity remain poorly understood. Perineuronal nets (PNNs) enwrapping PV+ cells are long-standing candidates for playing such a role, yet their precise contribution has remained elusive. We show that the PNN protein Brevican is a critical regulator of interneuron plasticity. We find that Brevican simultaneously controls cellular and synaptic forms of plasticity in PV+ cells by regulating the localization of potassium channels and AMPA receptors, respectively. By modulating Brevican levels, experience introduces precise molecular and cellular modifications in PV+ cells that are required for learning and memory. These findings uncover a molecular program through which a PNN protein facilitates appropriate behavioral responses to experience by dynamically gating PV+ interneuron function.
Neocortical epilepsy is frequently drug-resistant. Surgery to remove the epileptogenic zone is only feasible in a minority of cases, leaving many patients without an effective treatment. We report the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model in which epilepsy is induced by tetanus toxin injection in the motor cortex. By applying several complementary methods that use continuous wireless electroencephalographic monitoring to quantify epileptic activity, we observed increases in high frequency activity and in the occurrence of epileptiform events. Pyramidal neurons in the epileptic focus showed enhanced intrinsic excitability consistent with seizure generation. Optogenetic inhibition of a subset of principal neurons transduced with halorhodopsin targeted to the epileptic focus by lentiviral delivery was sufficient to attenuate electroencephalographic seizures. Local lentiviral overexpression of the potassium channel Kv1.1 reduced the intrinsic excitability of transduced pyramidal neurons. Coinjection of this Kv1.1 lentivirus with tetanus toxin fully prevented the occurrence of electroencephalographic seizures. Finally, administration of the Kv1.1 lentivirus to an established epileptic focus progressively suppressed epileptic activity over several weeks without detectable behavioral side effects. Thus, gene therapy in a rodent model can be used to suppress seizures acutely, prevent their occurrence after an epileptogenic stimulus, and successfully treat established focal epilepsy.
Gamma oscillations in the dentate gyrus and hippocampal CA3 show variable coherence in vivo, but the mechanisms and relevance for information flow are unknown. We found that carbacholinduced oscillations in rat CA3 have biphasic phase-response curves, consistent with the ability to couple with oscillations in afferent projections. Differences in response to stimulation of either the intrinsic feedback circuit or the dentate gyrus were well described by varying an impulse vector in a two-dimensional dynamical system, representing the relative input to excitatory and inhibitory neurons. Responses to sinusoidally modulated optogenetic stimulation confirmed that the CA3 network oscillation can entrain to periodic inputs, with a steep dependence of entrainment phase on input frequency. CA3 oscillations are therefore suited to coupling with oscillations in the dentate gyrus over a broad range of frequencies. Many brain areas, including the dentate gyrus and hippocampal CA3, show prominent gamma oscillations whose inter-region coherence varies during awake activity 1,2 . Structures of gamma-oscillatory activity in the temporal lobe are modulated by both brain state 3 and task demands 4,5 . Such changing patterns of coherent oscillatory activity may be involved in controlling information flow among connected networks 6-8 . The dynamical mechanisms underlying the emergence of coherence among anatomically coupled networks are, however, poorly understood.During gamma oscillations, individual neurons spike irregularly 1,2,9-11 , but the collective dynamics of the local network are oscillatory. Thus, the emergence of phase coherence between regions is a process of synchronization between local network oscillators. Important determinants of the synchronization properties of systems of coupled oscillators are the phase-response curves (PRCs) of the constituents 12-14 . Synchronization through excitatory connections is strongly promoted by biphasic PRCs, in which the same input can either advance or delay the phase of oscillation depending on when the perturbation occurs during the oscillatory cycle. Such PRCs allow oscillators to entrain to periodic inputs at both higher and lower frequencies than the unperturbed oscillation frequency. Although the mechanisms generating gamma oscillations in local networks have been extensively studied 9,11,15,16 , the phase response dynamics of the resulting network oscillators have not been measured, nor have their entrainment properties in response to periodic inputs been
Juvenile myoclonic epilepsy (JME) is characterized by excellent response to treatment, if diagnosed correctly. Lifestyle advice is an integral part of the treatment of JME; it should include recommendations on avoidance of common triggers such as sleep deprivation and alcohol excess and emphasis on the importance of compliance with medication. The drug of first choice in the treatment of JME is sodium valproate, which has a response rate of up to 80%. Valproate should be avoided in women of childbearing age because of significantly increased risks of fetal malformations and neurodevelopmental delay. Levetiracetam or lamotrigine are alternative first-line options if valproate is contraindicated. With limited data from trials to support either of these drugs, the choice should take into account comorbidity factors and patient priorities. Because of its low side effect profile, excellent tolerability, and lack of interactions with other drugs, levetiracetam is our preferred alternative first-line agent. Lamotrigine is another first-line option but may exacerbate myoclonus. The failure of valproate or failure of two first-line antiepileptic drugs suggests that combination therapy is indicated. Drug interactions and the patient's gender, age, and comorbidities need to be considered. Levetiracetam, lamotrigine, and valproate are suitable adjuncts, with a synergistic effect reported from the combination of valproate and lamotrigine. Clonazepam is a useful adjunct for myoclonus and can be used in combination with lamotrigine to avoid lamotrigine's myoclonic effects. In women of childbearing potential, valproate should be considered if levetiracetam and lamotrigine have failed to control seizures at this stage. Topiramate is a cost-effective alternative monotherapy, but because of its poor tolerability, we recommend it as add-on treatment only. Zonisamide should remain a second-line adjunct in the treatment of JME, owing to the lack of supportive data. Phenobarbital is the most cost-effective drug and can be used to control the seizures of JME when antiepileptic drugs are limited or too costly. Carbamazepine, oxcarbazepine, and phenytoin can exacerbate absences and myoclonus and are therefore contraindicated, although they can improve control of tonic-clonic seizures when these are refractory to other medication. Gabapentin, pregabalin, tiagabine, and vigabatrin are contraindicated and can worsen seizures. (Tiagabine and vigabatrin have been reported to induce absence status epilepticus.) Surgical alternatives in refractory cases are rarely contemplated but may include vagus nerve stimulation and callosotomy. Deep brain stimulation is an experimental technique that may prove useful in managing refractory cases of JME.
Advanced EEG review methods and source localization provide useful lateralizing information in difficult frontal lobe epilepsy seizure patterns.
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