KCNQ4 potassium channel subunit deletion leads to exaggerated acoustic startle reflex in mice.

The potassium voltage-gated channel subfamily Q member 4 (KCNQ4) subunit forms channels responsible for M-current, a muscarine-sensitive potassium current regulating neuronal excitability. In contrast to other KCNQ subunits, its expression is restricted to the cochlear outer hair cells, the auditory brainstem and other brainstem nuclei in a great overlap with structures involved in startle reflex. We aimed to show whether startle reflexis affected by the loss of KCNQ4 subunit and whether these alterations are similar to the ones caused by brainstem hyperexcitability. Young adult KCNQ4 knockout mice and wild-type littermates, as well as mice expressing hM3D chemogenetic actuator in the pontine caudal nucleus and neurons innervating it were used for testing acoustic startle. The acoustic startle reflex was significantly increased in knockout mice compared with wild-type littermates. When mice expressing human M3 muscarinic (hM3D) in nuclei related to startle reflex were tested, a similar increase of the first acoustic startle amplitude and a strong habituation of the further responses was demonstrated. We found that the acoustic startle reflex is exaggerated and minimal habituation occurs in KCNQ4 knockout animals. These changes are distinct from the effects of the hyperexcitability of nuclei involved in startle. One can conclude that the exaggerated startle reflex found with the KCNQ4 subunit deletion is the consequence of both the cochlear damage and the changes in neuronal excitability of startle networks.

Modulation of motor behavior by the mesencephalic locomotor region.

The mesencephalic locomotor region (MLR) serves as an interface between higher-order motor systems and lower motor neurons. The excitatory module of the MLR is composed of the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF), and their activation has been proposed to elicit different modalities of movement. However, how the differences in connectivity and physiological properties explain their contributions to motor activity is not well known. Here we report that CnF glutamatergic neurons are more electrophysiologically homogeneous than PPN neurons and have mostly short-range connectivity, whereas PPN glutamatergic neurons are heterogeneous and maintain long-range connections, most notably with the basal ganglia. Optogenetic activation of CnF neurons produces short-lasting muscle activation, driving involuntary motor activity. In contrast, PPN neuron activation produces long-lasting increases in muscle tone that reduce motor activity and disrupt gait. Our results highlight biophysical and functional attributes among MLR neurons that support their differential contribution to motor behavior.

Topographical Organization of M-Current on Dorsal and Median Raphe Serotonergic Neurons.

Dorsal and median raphe nuclei (DR and MR, respectively) are members of the reticular activating system and play important role in the regulation of the sleep-wakefulness cycle, movement, and affective states. M-current is a voltage-gated potassium current under the control of neuromodulatory mechanisms setting neuronal excitability. Our goal was to determine the proportion of DR and MR serotonergic neurons possessing M-current and whether they are organized topographically. Electrophysiological parameters of raphe serotonergic neurons influenced by this current were also investigated. We performed slice electrophysiology on genetically identified serotonergic neurons. Neurons with M-current are located rostrally in the DR and dorsally in the MR. M-current determines firing rate, afterhyperpolarization amplitude, and adaptation index (AI) of these neurons, but does not affect input resistance, action potential width, and high threshold oscillations.These findings indicate that M-current has a strong impact on firing properties of certain serotonergic neuronal subpopulations and it might serve as an effective contributor to cholinergic and local serotonergic neuromodulatory actions.

Orexinergic actions modify occurrence of slow inward currents on neurons in the pedunculopontine nucleus.

Orexins are neuromodulatory peptides of the lateral hypothalamus which regulate homeostatic mechanisms including sleep-wakefulness cycles. Orexinergic actions stabilize wakefulness by acting on the nuclei of the reticular activating system, including the pedunculopontine nucleus. Orexin application to pedunculopontine neurons produces a noisy tonic inward current and an increase in the frequency and amplitudes of excitatory postsynaptic currents. In the present project, we investigated orexinergic neuromodulatory actions on astrocyte-mediated neuronal slow inward currents of pedunculopontine neurons and their relationships with tonic currents by using slice electrophysiology on preparations from mice. We demonstrated that, in contrast to several other neuromodulatory actions and in line with literature data, orexin predominantly elicited a tonic inward current. A subpopulation of the pedunculopontine neurons possessed slow inward currents. Independently from the tonic currents, actions on slow inward currents were also detected, which resembled other neuromodulatory actions: if slow inward currents were almost absent on the neuron, orexin induced an increase of the charge movements by slow inward currents, whereas if slow inward current activity was abundant on the neurons, orexin exerted inhibitory action on it. Our data support the previous findings that orexin elicits only inward currents in contrast with cannabinoid, cholinergic or serotonergic actions. Similar to the aforementioned neuromodulatory actions, orexin influences slow inward currents in a way depending on control slow inward current activity. Furthermore, we found that orexinergic actions on slow inward currents are similarly independent from its actions on tonic currents, as it was previously found with other neuromodulatory agonists.