Sascha du Lac

Long-Lasting Increases in Intrinsic Excitability Triggered by Inhibition

Although experience-dependent changes in neural circuits are commonly assumed to be mediated by synaptic plasticity, modifications of intrinsic excitability may serve as a complementary mechanism. In whole-cell recordings from spontaneously firing vestibular nucleus neurons, brief periods of inhibitory synaptic stimulation or direct membrane hyperpolarization triggered long-lasting increases in spontaneous firing rates and firing responses to intracellular depolarization. These increases in excitability, termed firing rate potentiation, were induced by decreases in intracellular calcium and expressed as reductions in the sensitivity to the BK-type calcium-activated potassium channel blocker iberiotoxin. Firing rate potentiation is a novel form of cellular plasticity that could contribute to motor learning in the vestibulo-ocular reflex.

Decreases in CaMKII Activity Trigger Persistent Potentiation of Intrinsic Excitability in Spontaneously Firing Vestibular Nucleus Neurons

Calcium/calmodulin-dependent protein kinase II (CaMKII) has been described as a biochemical switch that is turned on by increases in intracellular calcium to mediate synaptic plasticity. Here, we show that reductions in CaMKII activity trigger persistent increases in intrinsic excitability. In spontaneously firing vestibular nucleus neurons, CaMKII activity is near maximal, and blockade of CaMKII activity increases excitability by reducing BK-type calcium-activated potassium currents. Firing rate potentiation, a form of plasticity in which synaptic inhibition induces long-lasting increases in excitability, is occluded by prior blockade of CaMKII and blocked by addition of constitutively active CaMKII. Reductions in CaMKII activity are necessary and sufficient to induce firing rate potentiation and may contribute to motor learning in the vestibulo-ocular reflex.

Intrinsic and synaptic plasticity in the vestibular system.

The vestibular system provides an attractive model for understanding how changes in cellular and synaptic activity influence learning and memory in a quantifiable behavior, the vestibulo-ocular reflex. The vestibulo-ocular reflex produces eye movements that compensate for head motion; simple yet powerful forms of motor learning calibrate the circuit throughout life. Learning in the vestibulo-ocular reflex depends initially on the activity of Purkinje cells in the cerebellar flocculus, but consolidated memories appear to be stored downstream of Purkinje cells, probably in the vestibular nuclei. Recent studies have demonstrated that the neurons of the vestibular nucleus possess the capacity for both synaptic and intrinsic plasticity. Mechanistic analyses of a novel form of firing rate potentiation in neurons of the vestibular nucleus have revealed new rules of plasticity that could apply to spontaneously firing neurons in other parts of the brain.

Comparison of plasticity and development of mouse optokinetic and vestibulo-ocular reflexes suggests differential gain control mechanisms.

Image stability during self-motion is achieved via a combination of the optokinetic and vestibulo-ocular reflexes (OKR and VOR). To determine whether distinct neuronal mechanisms are used to calibrate eye movements driven by visual and vestibular signals, we examined the developmental maturation and adaptive plasticity of the OKR and VOR in mice. The combined performance of the OKR and VOR, measured with infrared video oculography, produces nearly perfect gaze stability both in adult mice and in juveniles (postnatal days 21-26). Analyses of the OKR and VOR in isolation, however, indicate that VOR gains in juveniles are lower than in adult mice, while OKR gains are higher, indicating that juveniles rely more strongly on vision to stabilize gaze than do adults. Adaptive plasticity in the mouse OKR and VOR could be induced by 30 min of visual-vestibular mismatch training. Examination of the effects of training on the OKR and VOR revealed differential mechanisms and persistence of adaptive plasticity. Increases in VOR gain induced by rotating mice in the opposite direction to the visual surround were short-lasting and were accompanied by long-lasting increases in OKR gain. In contrast, decreases in VOR gain induced by rotating mice in the same direction as the visual surround were persistent and were accompanied by long-lasting increases in OKR gain. Vestibular training had little effect on either the OKR or VOR, while visual training induced robust and long-lasting increases in the OKR but had no effect on the VOR. These data indicate that multiple mechanisms of plasticity operate over distinct time courses to optimize oculomotor performance in mice.

The Beat Goes On: Spontaneous Firing in Mammalian Neuronal Microcircuits

Many neurons in the brain remain active even when an animal is at rest. Over the past few decades, it has become clear that, in some neurons, this activity can persist even when synaptic transmission is blocked and is thus endogenously generated. This “spontaneous” firing, originally described

Similar Properties of Transient, Persistent, and Resurgent Na Currents in GABAergic and Non-GABAergic Vestibular Nucleus Neurons

Sodium currents in fast firing neurons are tuned to support sustained firing rates >50-60 Hz. This is typically accomplished with fast channel kinetics and the ability to minimize the accumulation of Na channels into inactivated states. Neurons in the medial vestibular nuclei (MVN) can fire at exceptionally high rates, but their Na currents have never been characterized. In this study, Na current kinetics and voltage-dependent properties were compared in two classes of MVN neurons with distinct firing properties. Non-GABAergic neurons (fluorescently labeled in YFP-16 transgenic mice) have action potentials with faster rise and fall kinetics and sustain higher firing rates than GABAergic neurons (fluorescently labeled in GIN transgenic mice). A previous study showed that these neurons express a differential balance of K currents. To determine whether the Na currents in these two populations were different, their kinetics and voltage-dependent properties were measured in acutely dissociated neurons from 24- to 40-day-old mice. All neurons expressed persistent Na currents and large transient Na currents with resurgent kinetics tuned for fast firing. No differences were found between the Na currents expressed in GABAergic and non-GABAergic MVN neurons, suggesting that differences in properties of these neurons are tuned by their K currents.

Implementation of Linear Sensory Signaling via Multiple Coordinated Mechanisms at Central Vestibular Nerve Synapses

Signal transfer in neural circuits is dynamically modified by the recent history of neuronal activity. Short-term plasticity endows synapses with nonlinear transmission properties, yet synapses in sensory and motor circuits are capable of signaling linearly over a wide range of presynaptic firing rates. How do such synapses achieve rate-invariant transmission despite history-dependent nonlinearities? Here, ultrastructural, biophysical, and computational analyses demonstrate that concerted molecular, anatomical, and physiological refinements are required for central vestibular nerve synapses to linearly transmit rate-coded sensory signals. Vestibular synapses operate in a physiological regime of steady-state depression imposed by tonic firing. Rate-invariant transmission relies on brief presynaptic action potentials that delimit calcium influx, large pools of rapidly mobilized vesicles, multiple low-probability release sites, robust postsynaptic receptor sensitivity, and efficient transmitter clearance. Broadband linear synaptic filtering of head motion signals is thus achieved by coordinately tuned synaptic machinery that maintains physiological operation within inherent cell biological limitations.

Sensory and motor systems.

Rachel Wilson is an Associate Professor in the Department of Neurobiology at Harvard Medical School and an Early Career Scientist of the Howard Hughes Medical Institute. Dr. Wilson’s lab studies neural computations involved in early stages of sensory processing, with a focus on the olfactory and auditory systems of Drosophila. Her research aims to understand the cellular, synaptic, and circuit mechanisms that implement these computations, as well as the adaptive functions of these computations.