In central mammalian neurons, activation of metabotropic glutamate receptor type1 (mGluR1) evokes a complex synaptic response consisting of IP3 receptor-dependent Ca(2+) release from internal Ca(2+) stores and a slow depolarizing potential involving TRPC3 channels. It is largely unclear how mGluR1 is linked to its downstream effectors. Here, we explored the role of stromal interaction molecule 1 (STIM1) in regulating neuronal Ca(2+) signaling and mGluR1-dependent synaptic transmission. By analyzing mouse cerebellar Purkinje neurons, we demonstrate that STIM1 is an essential regulator of the Ca(2+) level in neuronal endoplasmic reticulum Ca(2+) stores. Both mGluR1-dependent synaptic potentials and IP3 receptor-dependent Ca(2+) signals are strongly attenuated in the absence of STIM1. Furthermore, the Purkinje neuron-specific deletion of Stim1 causes impairments in cerebellar motor behavior. Together, our results demonstrate that in the mammalian nervous system STIM1 is a key regulator of intracellular Ca(2+) signaling, metabotropic glutamate receptor-dependent synaptic transmission, and motor coordination.

Highlights d Conditional deletion of Na V 1.2 channels increases action potential (AP) excitability d Na V 1.2 regulates somatodendritc excitability, and Na V 1.6 regulates axonal action potential initiation d Lack of Na V 1.2 channels impairs AP repolarization by reducing K V activation d Reduced K V -mediated AP after hyperpolarization increases AP output

Neuronal excitability in the vertebrate brain is governed by the coordinated activity of both ligand- and voltage-gated ion channels. In the cerebellum, spontaneous action potential (AP) firing of inhibitory stellate cells (SCs) is variable, typically operating within the 5- to 30-Hz frequency range. AP frequency is shaped by the activity of somatodendritic A-type K + channels and the inhibitory effect of GABAergic transmission. An added complication, however, is that whole-cell recording from SCs induces a time-dependent and sustained increase in membrane excitability making it difficult to define the full range of firing rates. Here, we show that whole-cell recording in cerebellar SCs of both male and female mice augments firing rates by reducing the membrane potential at which APs are initiated. AP threshold is lowered due to a hyperpolarizing shift in the gating behavior of voltage-gated Na + channels. Whole-cell recording also elicits a hyperpolarizing shift in the gating behavior of A-type K + channels which contributes to increased firing rates. Hodgkin–Huxley modeling and pharmacological experiments reveal that gating shifts in A-type K + channel activity do not impact AP threshold, but rather promote channel inactivation which removes restraint on the upper limit of firing rates. Taken together, our work reveals an unappreciated impact of voltage-gated Na + channels that work in coordination with A-type K + channels to regulate the firing frequency of cerebellar SCs.

Neurotransmitter-gated ion channels are allosteric proteins that switch on and off in response to agonist binding. Most studies have focused on the agonist-bound, activated channel while assigning a lesser role to the apo or resting state. Here, we show that nanoscale mobility of resting a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (AMPA receptors) predetermines responsiveness to neurotransmitter, allosteric anions and TARP auxiliary subunits. Mobility at rest is regulated by alternative splicing of the flip/flop cassette of the ligand-binding domain, which controls motions in the distant AMPA receptor N-terminal domain (NTD). Flip variants promote moderate NTD movement, which establishes slower channel desensitization and robust regulation by anions and auxiliary subunits. In contrast, greater NTD mobility imparted by the flop cassette acts as a master switch to override allosteric regulation. In AMPA receptor heteromers, TARP stoichiometry further modifies these actions of the flip/flop cassette generating two functionally distinct classes of partially and fully TARPed receptors typical of cerebellar stellate and Purkinje cells.

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Cerebellar stellate cells form inhibitory synapses with Purkinje cells, the sole output of the cerebellum. Upon stimulation by a pair of varying inhibitory and fixed excitatory presynaptic inputs, these cells do not respond to excitation (i.e., do not generate an action potential) when the magnitude of the inhibition is within a given range, but they do respond outside this range. We previously used a revised Hodgkin–Huxley type of model to study the nonmonotonic first-spike latency of these cells and their temporal increase in excitability in whole cell configuration (termed run-up). Here, we recompute these latency profiles using the same model by adapting an efficient computational technique, the two-point boundary value problem, that is combined with the continuation method. We then extend the study to investigate how switching in responsiveness, upon stimulation with presynaptic inputs, manifests itself in the context of run-up. A three-dimensional reduced model is initially derived from the original six-dimensional model and then analyzed to demonstrate that both models exhibit type 1 excitability possessing a saddle-node on an invariant cycle (SNIC) bifurcation when varying the amplitude of [Formula: see text]. Using slow-fast analysis, we show that the original model possesses three equilibria lying at the intersection of the critical manifold of the fast subsystem and the nullcline of the slow variable [Formula: see text] (the inactivation of the A-type K[Formula: see text] channel), the middle equilibrium is of saddle type with two-dimensional stable manifold (computed from the reduced model) acting as a boundary between the responsive and non-responsive regimes, and the (ghost of) SNIC is formed when the [Formula: see text]-nullcline is (nearly) tangential to the critical manifold. We also show that the slow dynamics associated with (the ghost of) the SNIC and the lower stable branch of the critical manifold are responsible for generating the nonmonotonic first-spike latency. These results thus provide important insight into the complex dynamics of stellate cells.

The limbic system is presumed to have a central role in cognitive performance, in particular memory. The purpose of this study was to investigate the relationship between limbic white matter microstructure and neuropsychological function in temporal-lobe epilepsy (TLE) patients using diffusion tensor imaging (DTI). Twenty-one adult TLE patients, including 7 non-lesional (nlTLE) and 14 with unilateral mesial temporal sclerosis (uTLE), were studied with both DTI and hippocampal T2 relaxometry. Correlations were performed between fractional anisotropy (FA) of the bilateral fornix and cingulum, hippocampal T2, neuropsychological tests. Positive correlations were observed in the whole group for the left fornix and processing speed index. In contrast, memory tests did not show significant correlations with DTI findings. Subgroup analysis demonstrated an association between the left fornix and processing speed in nlTLE but not uTLE. No correlations were observed between hippocampal T2 and test scores in either the TLE group as a whole or after subgroup analysis. Our findings suggest that integrity of the left fornix specifically is an important anatomical correlate of cognitive function in TLE patients, in particular patients with nlTLE.

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