Clptm1 Downregulation Exerts Antiepileptic Activity by Regulating GABAAR-mediated Inhibitory Synaptic Transmission in PTZ-induced Epileptic Model

Background: Disruption of GABAAR synaptic clustering and a decrease number in their cell surface are thought to contribute to the alteration in the balance between excitatory and inhibitory neurotransmission, which contributes to seizure induction and propagation. Cleft lip and palate transmembrane protein 1 (Clptm1), a multi-pass transmembrane protein, has been showed that it is an intracellular molecule that controls forward trafficking of GABAAR. Clptm1 downregulating increased miniature inhibitory postsynaptic current (mIPSC) in vivo. Thus, Clptm1 controls phasic and tonic inhibitory transmission in brain. In this study, we hypothesized that Clptm1 may be involved in epileptic seizure by regulating GABAAR-mediated inhibitory synaptic transmission in epileptic model.Methods and Results: In PTZ-induced epileptic model, we found that Clptm1 was increased in temporal lobe epilepsy (TLE) patients as well as in epileptic model. Then, we showed that Clptm1 downregulation exerted antiepileptic activities in epileptic model, which was associated to the increased surface GABAARγ2 expression and mIPSCs amplitudes.Conclusions: Clptm1 downregulation exerted antiepileptic activities in epileptic model, thus, it may be a promising target for antiepileptic treatments.

Multibranch Formal Neuron: An Internally Nonlinear Learning Unit

The transformation of synaptic input into action potential in nerve cells is strongly influenced by the morphology of the dendritic arbor as well as the synaptic efficacy map. The multiplicity of dendritic branches strikingly enables a single cell to act as a highly nonlinear processing element. Studies have also found functional synaptic clustering whereby synapses that encode a common sensory feature are spatially clustered together on the branches. Motivated by these findings, here we introduce a multibranch formal model of the neuron that can integrate synaptic inputs nonlinearly through collective action of its dendritic branches and yields synaptic clustering. An analysis in support of its use as a computational building block is offered. Also offered is an accompanying gradient descent–based learning algorithm. The model unit spans a wide spectrum of nonlinearities, including the parity problem, and can outperform the multilayer perceptron in generalizing to unseen data. The occurrence of synaptic clustering boosts the generalization efficiency of the unit, which may also be the answer for the puzzling ubiquity of synaptic clustering in the real neurons. Our theoretical analysis is backed up by simulations. The study could pave the way to new artificial neural networks.

A unifying framework for synaptic organization on cortical dendrites

Dendritic synaptic inputs are organized into functional clusters with remarkable subcellular precision at the micron level. This organization emerges during early postnatal development through patterned spontaneous activity and manifests both locally where nearby synapses are significantly correlated, and globally with distance to the soma. We propose a biophysically motivated synaptic plasticity model to dissect the mechanistic origins of this organization during development, and elucidate synaptic clustering of different stimulus features in the adult. Our model captures local clustering of orientation in ferret vs. receptive field overlap in mouse visual cortex based on the cortical magnification of visual space. Including a back-propagating action potential explains branch clustering heterogeneity in the ferret, and produces a global retinotopy gradient from soma to dendrite in the mouse. Therefore, our framework suggests that sub-cellular precision in connectivity can already be established in development, and unifies different aspects of synaptic organization across species and scales.

Synaptic clustering differences due to different GABRB3 mutations cause variable epilepsy syndromes

Mutations in GABRB3, which encodes the β3 subunit of GABAA receptors, cause variable epilepsy syndromes with autism and intellectual disability. Shi et al. report that mutant β3 subunits reduce expression of wildtype γ2 subunits, which are critical for receptor synaptic clustering. However, they do so to different degrees, contributing to disease heterogeneity.