Mechanism of stress-induced attacks in an episodic neurologic disorder.

Stress is the most common trigger among episodic neurologic disorders. In episodic ataxia type 2 (EA2), physical or emotional stress causes episodes of severe motor dysfunction that manifest as ataxia and dystonia. We used the tottering (tg/tg) mouse, a faithful animal model of EA2, to dissect the mechanisms underlying stress-induced motor attacks. We find that in response to acute stress, activation of α1-adrenergic receptors (α1-Rs) on Purkinje cells by norepinephrine leads to their erratic firing and consequently motor attacks. We show that norepinephrine induces erratic firing of Purkinje cells by disrupting their spontaneous intrinsic pacemaking via a casein kinase 2 (CK2)-dependent signaling pathway, which likely reduces the activity of calcium-dependent potassium channels. Moreover, we report that disruption of this signaling cascade at a number of nodes prevents stress-induced attacks in the tottering mouse. Together, our results suggest that norepinephrine and CK2 are required for the initiation of stress-induced attacks in EA2 and provide previously unidentified targets for therapeutic intervention.

Aberrant cerebellar Purkinje cell activity as the cause of motor attacks in a mouse model of episodic ataxia type 2.

Many cerebellar-induced neurological disorders, such as ataxias and cerebellar-induced dystonias, are associated with abnormal Purkinje cell activity. In tottering mice, a well-established mouse model of episodic ataxia type 2 (EA2), cerebellar Purkinje cells are required for the initiation of motor attacks. How Purkinje cells contribute to the initiation of attacks is not known, and to date there are no reports on the activity of Purkinje cells during motor attacks in the tottering mice. Here, we show that tottering Purkinje cells exhibit high-frequency burst firing during attacks, reminiscent of other mouse models of cerebellar-induced motor dysfunction. We recorded the activity of Purkinje cells in awake head-restrained tottering mice at baseline, or during caffeine-induced attacks. During motor attacks, firing of Purkinje cells transformed to high-frequency burst firing. Interestingly, the extent to which the activity of Purkinje cells was erratic was correlated with the severity of the motor dysfunction. In support of a causal role for erratic activity in generating motor dysfunction, we found that direct infusion of the small conductance calcium-activated potassium (SK) channel activator NS309 into the cerebellum of tottering mice in the midst of an attack normalized the firing of Purkinje cells and aborted attacks. Conversely, we found that inducing high-frequency burst firing of Purkinje cells in wild-type animals is sufficient to produce severe motor signs. We report that erratic activity of wild-type Purkinje cells results in ataxia and dystonic postures. Moreover, this aberrant activity is the cause of motor attacks in the tottering mice.

Efficient generation of reciprocal signals by inhibition.

Reciprocal activity between populations of neurons has been widely observed in the brain and is essential for neuronal computation. The different mechanisms by which reciprocal neuronal activity is generated remain to be established. A common motif in neuronal circuits is the presence of afferents that provide excitation to one set of principal neurons and, via interneurons, inhibition to a second set of principal neurons. This circuitry can be the substrate for generation of reciprocal signals. Here we demonstrate that this equivalent circuit in the cerebellar cortex enables the reciprocal firing rates of Purkinje cells to be efficiently generated from a common set of mossy fiber inputs. The activity of a mossy fiber is relayed to Purkinje cells positioned immediately above it by excitatory granule cells. The firing rates of these Purkinje cells increase as a linear function of mossy fiber, and thus granule cell, activity. In addition to exciting Purkinje cells positioned immediately above it, the activity of a mossy fiber is relayed to laterally positioned Purkinje cells by a disynaptic granule cell → molecular layer interneuron pathway. Here we show in acutely prepared cerebellar slices that the input-output relationship of these laterally positioned Purkinje cells is linear and reciprocal to the first set. A similar linear input-output relationship between decreases in Purkinje cell firing and strength of stimulation of laterally positioned granule cells was also observed in vivo. Use of interneurons to generate reciprocal firing rates may be a common mechanism by which the brain generates reciprocal signals.