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The kindling model has been used extensively by researchers to study the neurobiology of temporal lobe epilepsy (TLE) due to its capacity to induce intensification of seizures by the progressive recruitment of additional neuronal clusters into epileptogenic networks. We applied repetitive focal optogenetic activation of putative excitatory neurons in the dorsal CA1 area of the hippocampus of mice to investigate the role of inhibitory signaling during this process. This experimental protocol resulted in a kindling phenotype that was maintained for 2weeks after the animals were fully kindled. As a result of the different phases of optogenetic kindling (OpK), key inhibitory signaling elements, such as KCC2 and NKCC1, exhibited distinct temporal and spatial dynamics of regulation. These alterations in protein expression were related to the distinct pattern of ictal activity propagation through the different hippocampal sublayers. Our results suggest the KCC2 disruption in the contralateral hippocampus of fully kindled animals progressively facilitated the creation of pathological pathways for seizure propagation through the hippocampal network. Upon completion of kindling, we observed animals that were restimulated after a rest period of 14-day showed, besides a persistent KCC2 downregulation, an NKCC1 upregulation in the bilateral dentate gyrus and hippocampus-wide loss of parvalbumin-positive interneurons. These alterations observed in the chronic phase of OpK suggest that the hippocampus of rekindled animals continued to undergo self-modifications during the rest period. The changes resulting from this period suggest the possibility of the development of a mirror focus on the hippocampus contralateral to the site of optical stimulations. Our results offer perspectives for preventing the recruitment and conversion of healthy neuronal networks into epileptogenic ones among patients with epilepsy. [ABSTRACT FROM AUTHOR]

The kindling model has been used extensively by researchers to study the neurobiology of temporal lobe epilepsy (TLE) due to its capacity to induce intensification of seizures by the progressive recruitment of additional neuronal clusters into epileptogenic networks. We applied repetitive focal optogenetic activation of putative excitatory neurons in the dorsal CA1 area of the hippocampus of mice to investigate the role of inhibitory signaling during this process. This experimental protocol resulted in a kindling phenotype that was maintained for 2 weeks after the animals were fully kindled. As a result of the different phases of optogenetic kindling (OpK), key inhibitory signaling elements, such as KCC2 and NKCC1, exhibited distinct temporal and spatial dynamics of regulation. These alterations in protein expression were related to the distinct pattern of ictal activity propagation through the different hippocampal sublayers. Our results suggest the KCC2 disruption in the contralateral hippocampus of fully kindled animals progressively facilitated the creation of pathological pathways for seizure propagation through the hippocampal network. Upon completion of kindling, we observed animals that were restimulated after a rest period of 14-day showed, besides a persistent KCC2 downregulation, an NKCC1 upregulation in the bilateral dentate gyrus and hippocampus-wide loss of parvalbumin-positive interneurons. These alterations observed in the chronic phase of OpK suggest that the hippocampus of rekindled animals continued to undergo self-modifications during the rest period. The changes resulting from this period suggest the possibility of the development of a mirror focus on the hippocampus contralateral to the site of optical stimulations. Our results offer perspectives for preventing the recruitment and conversion of healthy neuronal networks into epileptogenic ones among patients with epilepsy.

In this paper, we study the behavior of boundary droplets in a compact domain for a self-organizing inhibitory system based on the Ohta-Kawasaki diblock copolymer theory. The free energy of the system is a sum of a local term that favors sets with boundaries that minimize perimeter and a nonlocal term related to a Green's function with Neumann boundary condition. The solutions of this system depend on the domain Ω through the Green's function, the curvature κ(ξ) for ξ ∈ ∂Ω, and an interaction parameter γ that multiplies the nonlocal term. The interplay between these factors influences the types of equilibria that are possible. When γ is small, a single stationary boundary droplet tends to a location ξ∗ ∈ ∂Ω that maximizes κ(ξ). When γ is large compared to the droplet size, the droplet tends to a location that minimizes Rb(ξ, ξ) - a function related to the Green's function of the domain. In the intermediate case, the droplet locates near a point that minimizes Jb - a function involving both κ and Rb. When γ is sufficiently large, equilibrium configurations consisting of droplet assemblies exist, and we discuss the location of these droplets as well. We will focus on domains conformal to the unit disk and specifically an ellipse Ea with semimajor axis a > 1. We examine the sharp interface problem and utilize its solutions to determine the location of the boundary droplets. For an ellipse, we find Rb has two local minima co-located at the points which minimize κ(ξ). The sharp interface theory is developed under the condition that a droplet radius is sufficiently small. To investigate droplets of moderate size, we compute finite element solutions of the diffuse interface model of the Ohta-Kawasaki equations and demonstrate that the numerical solutions of the finite element model inherit the properties exhibited by solutions of the sharp interface model. For the diffuse interface model, we consider a variety of numerical solutions, including a single droplet and assemblies with as many 20 droplets. [ABSTRACT FROM AUTHOR]

Cognitive impairment in Down syndrome (DS) involves the hippocampus. In the Ts65Dn mouse model of DS, deficits in hippocampus-dependent learning and synaptic plasticity were linked to enhanced inhibition. However, the mechanistic basis of changes in inhibitory efficiency remains largely unexplored, and efficiency of the GABAergic synaptic neurotransmission has not yet been investigated in direct electrophysiological experiments. To investigate this important feature of neurobiology of DS, we examined synaptic and molecular properties of the GABAergic system in the dentate gyrus (DG) of adult Ts65Dn mice. Both GABAA and GABAB receptor-mediated components of evoked inhibitory postsynaptic currents (IPSCs) were significantly increased in Ts65Dn vs. control (2N) DG granule cells. These changes were unaccompanied by alterations in hippocampal levels of GABAA (α1, α2, α3, α5 and γ2) or GABAB (Gbr1a and Gbr1b) receptor subunits. Immunoreactivity for GAD65, a marker for GABAergic terminals, was also unchanged. In contrast, there was a marked change in functional parameters of GABAergic synapses. Paired stimulations showed reduced paired-pulse ratios of both GABAA and GABAB receptor-mediated IPSC components (IPSC2/IPSC1), suggesting an increase in presynaptic release of GABA. Consistent with increased gene dose, the level of the Kir3.2 subunit of potassium channels, effectors for postsynaptic GABAB receptors, was increased. This change was associated with enhanced postsynaptic GABAB/Kir3.2 signaling following application of the GABAB receptor agonist baclofen. Thus, both GABAA and GABAB receptor-mediated synaptic efficiency is increased in the Ts65Dn DG, thus likely contributing to deficient synaptic plasticity and poor learning in DS.

A ternary inhibitory system contains two terms in its free energy: the interface energy that favors microdomain growth and the longer ranging confinement energy that prevents unlimited spreading. In a parameter regime where two constituents are small in size compared to the third constituent and the longer ranging energy does not dominate, there is a double-bubble-like stable stationary point of the energy functional. The two minority constituents occupy the two bubbles of the double bubble, respectively, and the majority constituent fills the background. A special way of perturbing an exact double bubble leads to a restricted class of perturbed double bubbles that can be described by internal variables which are elements in a Hilbert space. The exact double bubble is nondegenerate in this class and nearby there is a perturbed double bubble that locally minimizes the free energy within the restricted class. This perturbed double bubble satisfies three of the four equations for stationary points of the free energy, namely, the three equations involving the curvature and the inhibitor variables on its three boundary curves. However it does not satisfy the 120 degree angle condition at its triple points. By translating and rotating the entire restricted class of perturbed double bubbles, one finds a particular direction and location in the domain of the problem where the locally minimizing perturbed double bubble in this specific restricted class also satisfies the 120 degree condition. This approach can handle both asymmetric and symmetric double bubbles. [ABSTRACT FROM AUTHOR]

Abstract: Cognitive impairment in Down syndrome (DS) involves the hippocampus. In the Ts65Dn mouse model of DS, deficits in hippocampus-dependent learning and synaptic plasticity were linked to enhanced inhibition. However, the mechanistic basis of changes in inhibitory efficiency remains largely unexplored, and efficiency of the GABAergic synaptic neurotransmission has not yet been investigated in direct electrophysiological experiments. To investigate this important feature of neurobiology of DS, we examined synaptic and molecular properties of the GABAergic system in the dentate gyrus (DG) of adult Ts65Dn mice. Both GABAA and GABAB receptor-mediated components of evoked inhibitory postsynaptic currents (IPSCs) were significantly increased in Ts65Dn vs. control (2N) DG granule cells. These changes were unaccompanied by alterations in hippocampal levels of GABAA (α1, α2, α3, α5 and γ2) or GABAB (Gbr1a and Gbr1b) receptor subunits. Immunoreactivity for GAD65, a marker for GABAergic terminals, was also unchanged. In contrast, there was a marked change in functional parameters of GABAergic synapses. Paired stimulations showed reduced paired-pulse ratios of both GABAA and GABAB receptor-mediated IPSC components (IPSC2/IPSC1), suggesting an increase in presynaptic release of GABA. Consistent with increased gene dose, the level of the Kir3.2 subunit of potassium channels, effectors for postsynaptic GABAB receptors, was increased. This change was associated with enhanced postsynaptic GABAB/Kir3.2 signaling following application of the GABAB receptor agonist baclofen. Thus, both GABAA and GABAB receptor-mediated synaptic efficiency is increased in the Ts65Dn DG, thus likely contributing to deficient synaptic plasticity and poor learning in DS. [Copyright &y& Elsevier]

The involvement of inhibitory transmitters for Ptychodiscus brevis toxin (PbTx)-induced depression of spinal synaptic transmission in neonatal rats was investigated. Stimulation of a dorsal root evoked monosynaptic reflex (MSR) and polysynaptic reflex (PSR) potentials in the segmental ventral root. The PbTx depressed the reflexes in a concentration-dependent manner and the depression was blocked by GABAA antagonist, bicuculline (1 μM). GABA also produced depression of the reflexes in a concentration-dependent manner. Simultaneous application of submaximal concentrations of PbTx (28 μM) and GABA (30 μM) enhanced the depression (>75%). In contrast, PbTx alone (28 μM) depressed the MSR and the PSR by 33 and 47%, respectively, and GABA (30 μM) alone depressed the reflexes by 30%. The N-methyl-d-aspartate receptor antagonist, dl-2-amino-5-phosphono-pentanoic acid (10 μM), blocked the PbTx-induced depression of MSR and also the enhancement of GABA response by PbTx. A glycine receptor antagonist, strychnine (1 μM), failed to block the depression by the toxin up to 28 μM; however, the depression was attenuated significantly at 84 μM of the toxin. The results indicate that PbTx depressed the spinal reflexes via GABAA receptors. Furthermore, the potentiation of GABAergic action by PbTx requires the N-methyl-d-aspartate dependent mechanism. [Copyright &y& Elsevier]

The aim of the present study was to evaluate the profile of cognitive impairment in patients with cortical cerebellar atrophy (CCA) by measurement of event-related potentials (ERP) and neuropsychological tests. We studied 13 CCA patients and 13 age-, sex- and education-matched normal controls. For ERP recording, we used the conventional auditory oddball task as well as the continuous performance task, which evaluates the attentional performance and ability to control a motor response, i.e., to execute (‘Go’) or inhibit a motor reaction (‘No Go’). Brain electric activity was recorded using 20 scalp electrodes and computed into series of potential distribution maps. For components of ERP, reference-independent measures [global field power (GFP)] were determined, and low-resolution brain electromagnetic tomography (LORETA) was used to compute the three-dimensional intracerebral distribution of electric activity of the P3 component of Go and No Go responses. A comprehensive neuropsychological test battery was also assessed. GFP peak latency was prolonged and GFP peak was attenuated under the No Go condition in patients with CCA, although there were no differences in the auditory oddball task and in the Go condition between the two groups. LORETA showed low activation of frontal source in CCA patients in No Go P3 compared with the controls. However, neuropsychological tests revealed no differences between the two groups. Our results indicate that degeneration of the cerebellum contributes to frontal dysfunction, and suggest this dysfunction is characterized by an impairment of the inhibitory system.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study investigated the effect of strio-nigral hemitransection on the enzymes necessary for the synthesis and cataboiism of γ-aminobutyric acid, acetylcholine and dopamine in the caudate nucleus, the putamen, the pallidum and the substantia nigra of the baboon. After transection, more than 70% of the L-glutamate decarboxylase activity was missing from the substantia nigra ipsilateral to the location of the lesions, leaving all remaining regions unchanged. Choline acetyltransferase, acetylcholinesterase and monoaminoxidase activities failed, however, to be affected by the lesions, while glutamic-γ-aminobutyric transaminase was slightly decreased in the substantia nigra. These results strongly support our previous view that the strio-nigral neuron system is primarily an inhibitory one, in which γ-aminobutyric acid plays the role of transmitter. Confirming earlier investigations, a marked reduction of L-DOPA decarboxylase activity was induced by the lesions in the caudate nucleus and the putamen, which indicates that the nigro-striatal neuron system in the baboon is also dopaminergic. Neither the striatum nor the substantia nigra had a markedly diminished acetylcholine content after hemitransection. This strongly suggests that the acetylcholine in the striatum does not depend on the integrity of the strio-nigral connexions. [ABSTRACT FROM AUTHOR]

Bruxism is an excessive clenching and involuntary parafunctional grinding of the teeth during sleep. It can cause damage to dental structures and temporomandibular joint dysfunction. An evaluation was performed on the effects over the masseter and temporalis anterior muscles in subjects with and without bruxism when electrical stimulation is applied to the right mental nerve. The results showed that, on average, the percentage decrease in the bruxist group for the right masseter was 25.02% and for the left masseter 25.87%. These results indicate that the inhibitory system produces an important decrease in the electrical activity of the two muscles, so it is a good starting point for a possible treatment in patients with bruxism and to develop new electronic stimulators. [ABSTRACT FROM AUTHOR]