Demonstration that sublinear dendrites enable linearly non-separable computations.

Theory predicts that nonlinear summation of synaptic potentials within dendrites allows neurons to perform linearly non-separable computations (LNSCs). Using Boolean analysis approaches, we predicted that both supralinear and sublinear synaptic summation could allow single neurons to implement a type of LNSC, the feature binding problem (FBP), which does not require inhibition contrary to the exclusive-or function (XOR). Notably, sublinear dendritic operations enable LNSCs when scattered synaptic activation generates increased somatic spike output.

RPM: An open-source Rotation Platform for open- and closed-loop vestibular stimulation in head-fixed Mice.

Head fixation allows the recording and presentation of controlled stimuli and is used to study neural processes underlying spatial navigation. However, it disrupts the head direction system because of the lack of vestibular stimulation. To overcome this limitation, we developed a novel rotation platform which can be driven by the experimenter (open-loop) or by animal movement (closed-loop).

Quantitative analysis of rabies virus-based synaptic connectivity tracing.

Monosynaptically restricted rabies viruses have been used for more than a decade for synaptic connectivity tracing. However, the verisimilitude of quantitative conclusions drawn from these experiments is largely unknown. The primary reason is the simple metrics commonly used, which generally disregard the effect of starter cell numbers.

Caβ surface charged residues contribute to the regulation of neuronal calcium channels.

Voltage-gated calcium channels are essential regulators of brain function where they support depolarization-induced calcium entry into neurons. They consist of a pore-forming subunit (Caα) that requires co-assembly with ancillary subunits to ensure proper functioning of the channel. Among these ancillary subunits, the Caβ plays an essential role in regulating surface expression and gating of the channels.

Differential Dendritic Integration of Synaptic Potentials and Calcium in Cerebellar Interneurons.

Dendritic voltage integration determines the transformation of synaptic inputs into output firing, while synaptic calcium integration drives plasticity mechanisms thought to underlie memory storage. Dendritic calcium integration has been shown to follow the same synaptic input-output relationship as dendritic voltage, but whether similar operations apply to neurons exhibiting sublinear voltage integration is unknown. We examined the properties and cellular mechanisms of these dendritic operations in cerebellar molecular layer interneurons using dendritic voltage and calcium imaging, in combination with synaptic stimulation or glutamate uncaging.

A Role for Synaptic Input Distribution in a Dendritic Computation of Motion Direction in the Retina.

The starburst amacrine cell in the mouse retina presents an opportunity to examine the precise role of sensory input location on neuronal computations. Using visual receptive field mapping, glutamate uncaging, two-photon Ca(2+) imaging, and genetic labeling of putative synapses, we identify a unique arrangement of excitatory inputs and neurotransmitter release sites on starburst amacrine cell dendrites: the excitatory input distribution is skewed away from the release sites. By comparing computational simulations with Ca(2+) transients recorded near release sites, we show that this anatomical arrangement of inputs and outputs supports a dendritic mechanism for computing motion direction.

Contribution of sublinear and supralinear dendritic integration to neuronal computations.

Nonlinear dendritic integration is thought to increase the computational ability of neurons. Most studies focus on how supralinear summation of excitatory synaptic responses arising from clustered inputs within single dendrites result in the enhancement of neuronal firing, enabling simple computations such as feature detection. Recent reports have shown that sublinear summation is also a prominent dendritic operation, extending the range of subthreshold input-output (sI/O) transformations conferred by dendrites.

The alpha2delta ligand gabapentin inhibits the Rab11-dependent recycling of the calcium channel subunit alpha2delta-2.

The α2δ subunits of voltage-gated calcium channels are important modulatory subunits that enhance calcium currents and may also have other roles in synaptogenesis. The antiepileptic and antiallodynic drug gabapentin (GBP) binds to the α2δ-1 and α2δ-2 isoforms of this protein, and its binding may disrupt the binding of an endogenous ligand, required for their correct function. We have shown previously that GBP produces a chronic inhibitory effect on calcium currents by causing a reduction in the total number of α2δ and α1 subunits at the cell surface.

A new look at calcium channel α2δ subunits.

The classical roles of α(2)δ proteins are as accessory calcium channel subunits, enhancing channel trafficking. They were thought to have type-I transmembrane topology, but we find that they can form GPI-anchored proteins. Moreover α(2)δ-1 and α(2)δ-3 have been shown to have novel functions in synaptogenesis, independent of their effect on calcium channels.

The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin.

Neuropathic pain results from damage to the peripheral sensory nervous system, which may have a number of causes. The calcium channel subunit alpha(2)delta-1 is upregulated in dorsal root ganglion (DRG) neurons in several animal models of neuropathic pain, and this is causally related to the onset of allodynia, in which a non-noxious stimulus becomes painful. The therapeutic drugs gabapentin and pregabalin (PGB), which are both alpha(2)delta ligands, have antiallodynic effects, but their mechanism of action has remained elusive.

Time course and specificity of the pharmacological disruption of the trafficking of voltage-gated calcium channels by gabapentin.

The mechanism of action of gabapentin is still not well understood. It binds to the alpha(2)delta-1 and alpha(2)delta-2 subunits of voltage-gated calcium channels but has little acute effect on calcium currents in several systems. However, our recent results conclusively demonstrated that gabapentin inhibited calcium currents when applied chronically but not acutely, both in heterologous expression systems and in dorsal root ganglion neurons.

Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin.

The mechanism of action of the antiepileptic and antinociceptive drugs of the gabapentinoid family has remained poorly understood. Gabapentin (GBP) binds to an exofacial epitope of the alpha(2)delta-1 and alpha(2)delta-2 auxiliary subunits of voltage-gated calcium channels, but acute inhibition of calcium currents by GBP is either very minor or absent. We formulated the hypothesis that GBP impairs the ability of alpha(2)delta subunits to enhance voltage-gated Ca(2+)channel plasma membrane density by means of an effect on trafficking.

Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels.

In this review, we examine what is known about the mechanism of action of the auxiliary alpha2delta subunits of voltage-gated Ca(2+) (Ca(v)) channels. First, to provide some background on the alpha2delta proteins, we discuss the genes encoding these channels, in addition to the topology and predicted structure of the alpha2delta subunits. We then describe the effects of alpha2delta subunits on the biophysical properties of Ca(v) channels and their physiological function.

The calcium channel alpha2delta-2 subunit partitions with CaV2.1 into lipid rafts in cerebellum: implications for localization and function.

The accessory alpha2delta subunits of voltage-gated calcium channels are highly glycosylated transmembrane proteins that interact with calcium channel alpha1 subunits to enhance calcium currents. We compared the membrane localization and processing of native cerebellar alpha2delta-2 subunits with alpha2delta-2 stably expressed in tsA-201 cells. We identified that alpha2delta-2 is completely concentrated in cholesterol-rich microdomains (lipid rafts) in cerebellum, in which it substantially colocalizes with the calcium channel alpha1 subunit CaV2.