Trpm5 channels encode bistability of spinal motoneurons and ensure motor control of hindlimbs in mice

Bistable motoneurons of the spinal cord exhibit warmth-activated plateau potential driven by Na+ and triggered by a brief excitation. The thermoregulating molecular mechanisms of bistability and their role in motor functions remain unknown. Here, we identify thermosensitive Na+-permeable Trpm5 channels as the main molecular players for bistability in mouse motoneurons. Pharmacological, genetic or computational inhibition of Trpm5 occlude bistable-related properties (slow afterdepolarization, windup, plateau potentials) and reduce spinal locomotor outputs while central pattern generators for locomotion operate normally. At cellular level, Trpm5 is activated by a ryanodine-mediated Ca2+ release and turned off by Ca2+ reuptake through the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump. Mice in which Trpm5 is genetically silenced in most lumbar motoneurons develop hindlimb paresis and show difficulties in executing high-demanding locomotor tasks. Overall, by encoding bistability in motoneurons, Trpm5 appears indispensable for producing a postural tone in hindlimbs and amplifying the locomotor output.

Rapid synaptic plasticity contributes to a learned conjunctive code of position and choice-related information in the hippocampus

To successfully perform goal-directed navigation, animals must know where they are and what they are doing, e.g., looking for water, bringing food back to the nest, or escaping from a predator. Hippocampal neurons code for these critical variables conjunctively, but little is known about how this where/what code is formed or flexibly routed to other brain regions. To address these questions, we performed intracellular whole-cell recordings in mouse CA1 during a cued, two-choice virtual navigation task. We demonstrate that plateau potentials in CA1 pyramidal neurons rapidly strengthen synaptic inputs carrying conjunctive information about position and choice. Plasticity-induced response fields were modulated by cues only in animals previously trained to collect rewards based on these cues. Thus, we reveal that gradual learning is required for the formation of a conjunctive population code, upstream of CA1, while plateau-potential-induced synaptic plasticity in CA1 enables flexible routing of the code to downstream brain regions.

Local glutamate-mediated dendritic plateau potentials change the state of the cortical pyramidal neuron

In cortical pyramidal neurons, we recorded glutamate-mediated dendritic plateau potentials with voltage imaging and created a computer model that recreated experimental measures from dendrite and cell body. Our model made new predictions, which were then tested in experiments. Plateau potentials profoundly change neuronal state: a plateau potential triggered in one basal dendrite depolarizes the soma and shortens membrane time constant, making the cell more susceptible to firing triggered by other afferent inputs.

Repetitive doublet firing in human motoneurons: evidence for interaction between common synaptic drive and plateau potential in natural motor control

The firing behavior of spinal motoneurons (MNs) is a result of processing synaptic inputs by MN membrane properties, including plateau potentials, fundamentally explored in animals. However, there is much less data about a plateau potential role in human motor control. We explored human MN repetitive doublet firing during gentle isometric voluntary muscle contractions with the aim of revealing possible evidence for interaction between plateau potentials and common synaptic drive known as an important determinant of MN pool firing behavior. Single-motor unit (MU) repetitive firing of trapezius and triceps brachii was analyzed. Subjects were asked to recruit MUs capable of firing repetitive doublets. The analysis of interspike intervals (ISIs) of background firing of simultaneously recorded MUs showed that beyond doublet series ISIs varied, often in unison with significant correlation coefficients, demonstrating common synaptic drive. During doublet series, MUs showed persistent doublet ISIs (typically 4–7 ms) and a tendency to increase the number of doublets in series throughout the experiment. This was consistent with involvement of MN plateau potentials resulting in persistent delayed depolarization (underlying each doublet) and warm-up effect. Common synaptic drive “started” doublet series; probably both mechanisms controlled postdoublet ISIs. However, convincing effects of plateau potentials on MU firing behavior during single firing were not found. Thus our results suggest a plateau potential role in specifying the essential firing pattern, doubling, of some MUs rather than its effect on firing behavior of the MN pool, on the whole, during voluntary muscle contractions in humans. NEW & NOTEWORTHY Properties of human motoneuron repetitive doublet firing were explored during voluntary muscle contractions. It was shown for the first time that these properties seem to be consistent with properties of both plateau potentials, resulting in persistent delayed depolarization (underlying each doublet) and common synaptic drive, starting this unusual firing; both mechanisms could probably control postdoublet intervals. A convincing effect of plateau potentials on motoneuron single-spike firing, despite doublet firing, was not found.

Cell-type–specific inhibition of the dendritic plateau potential in striatal spiny projection neurons

Striatal spiny projection neurons (SPNs) receive convergent excitatory synaptic inputs from the cortex and thalamus. Activation of spatially clustered and temporally synchronized excitatory inputs at the distal dendrites could trigger plateau potentials in SPNs. Such supralinear synaptic integration is crucial for dendritic computation. However, how plateau potentials interact with subsequent excitatory and inhibitory synaptic inputs remains unknown. By combining computational simulation, two-photon imaging, optogenetics, and dual-color uncaging of glutamate and GABA, we demonstrate that plateau potentials can broaden the spatiotemporal window for integrating excitatory inputs and promote spiking. The temporal window of spiking can be delicately controlled by GABAergic inhibition in a cell-type–specific manner. This subtle inhibitory control of plateau potential depends on the location and kinetics of the GABAergic inputs and is achieved by the balance between relief and reestablishment of NMDA receptor Mg2+ block. These findings represent a mechanism for controlling spatiotemporal synaptic integration in SPNs.

Postnatal emergence of serotonin-induced plateau potentials in commissural interneurons of the mouse spinal cord

Most studies of the mouse hindlimb locomotor network have used neonatal (P0–5) mice. In this study, we examine the postnatal development of intrinsic properties and serotonergic modulation of intersegmental commissural interneurons (CINs) from the neonatal period (P0–3) to the time the animals bear weight (P8–10) and begin to show adult walking (P14–16). CINs show an increase in excitability with age, associated with a decrease in action potential halfwidth and appearance of a fast component to the afterhyperpolarization at P14–16. Serotonin (5-HT) depolarizes and increases the excitability of most CINs at all ages. The major developmental difference is that serotonin can induce plateau potential capability in P14–16 CINs, but not at younger ages. These plateau potentials are abolished by nifedipine, suggesting that they are mediated by an L-type calcium current, ICa(L). Voltage-clamp analysis demonstrates that 5-HT increases a nifedipine-sensitive voltage-activated calcium current, ICa(V), in P14–16 CINs but does not increase ICa(V) in P8–10 CINs. These results, together with earlier work on 5-HT effects on neonatal CINs, suggest that 5-HT increases the excitability of CINs at all ages studied, but by opposite effects on calcium currents, decreasing N- and P/Q-type calcium currents and, indirectly, calcium-activated potassium current, at P0–3 but increasing ICa(L) at P14–16.

Heterogeneous firing behavior during ictal-like epileptiform activity in vitro

Seizure activity in vivo is caused by populations of neurons displaying a high degree of variability in activity pattern during the attack. The reason for this variability is not well understood. Here we show in an in vitro preparation that hippocampal CA1 pyramidal cells display four types of afterdischarge behavior during stimulus-induced ictal-like events in the presence of Cs+ (5 mM): type I (43.7%) consisting of high-frequency firing riding on a plateau potential; type II (28.2%) consisting of low-frequency firing with no plateau potential; type III (18.3%) consisting of high-frequency firing with each action potential preceded by a transient hyperpolarization and time-locked to population activity, no plateau potential; “passive” (9.9%) typified by no afterdischarge. Type I behavior was blocked by TTX (0.2 μM) and intracellular injection of QX314 (12.5–25 mM). TTX (0.2 μM) or phenytoin (50 μM) terminated ictal-like events, suggesting that the persistent Na+ current ( INaP) is pivotal for type I behavior. Type I behavior was not correlated to intrinsic bursting capability. Blockade of the M current ( IM) with linopirdine (10 μM) increased the ratio of type I neurons to 100%, whereas enhancing IM with retigabine (50–100 μM) greatly reduced the epileptiform activity. These results suggest an important role of IM in determining afterdischarge behavior through control of INaP expression. We propose that type I neurons act as pacemakers, which, through synchronization, leads to recruitment of type III neurons. Together, they provide the “critical mass” necessary for ictogenesis to become regenerative.