Role of GluR1 in activity-dependent motor system development.

Activity-dependent specification of neuronal architecture during early postnatal life is essential for refining the precision of communication between neurons. In the spinal cord under normal circumstances, the AMPA receptor subunit GluR1 is expressed at high levels by motor neurons and surrounding interneurons during this critical developmental period, although the role it plays in circuit formation and locomotor behavior is unknown. Here, we show that GluR1 promotes dendrite growth in a non-cell-autonomous manner in vitro and in vivo. The mal-development of motor neuron dendrites is associated with changes in the pattern of interneuronal connectivity within the segmental spinal cord and defects in strength and endurance. Transgenic expression of GluR1 in adult motor neurons leads to dendrite remodeling and supernormal locomotor function. GluR1 expression by neurons within the segmental spinal cord plays an essential role in formation of the neural network that underlies normal motor behavior.

Noise exposure enhances auditory cortex responses related to hyperacusis behavior.

Hyperacusis, a marked intolerance to normal environmental sound, is a common symptom in patients with tinnitus, Williams syndrome, autism, and other neurologic diseases. It has been suggested that an imbalance of excitation and inhibition in the central auditory system (CAS) may play an important role in hyperacusis. Recent studies found that noise exposure, one of the most common causes of hearing loss and tinnitus, can increase the auditory cortex (AC) response, presumably by increasing the gain of the AC. However, it is not clear whether the increased cortical response will affect sound sensitivity and induce hyperacusis. In this experiment, we studied the effects of noise exposure (narrow band noise, 12 kHz, 120 dB SPL, 1 hour) on the physiological response of the inferior colliculus (IC) and the AC, and the behavioral sound reaction in conscious Sprague Dawley rats. Noise exposure induced a decrease of sound evoked potential in the IC. However, significant increases of AC response including sound evoked potentials and the spike firing rates of AC neurons were recorded right after the noise exposure. These results suggest that noise exposure induces hyperexcitability of AC presumably by increasing the post-synaptic response of AC neurons. The behavioral consequence of the noise exposure on sound perception was measured by the amplitude of the acoustic startle response before and after noise exposure in a separate group of rats. Although noise exposure caused a moderate hearing loss, the acoustic startle amplitude at the super-threshold level was significantly increased. These results suggest that noise exposure can cause exaggerated the sound reaction which may be related with the enhanced responsiveness of the AC neurons. This phenomenon may be related with noise induced hyperacusis.This article is part of a Special Issue entitled: Tinnitus Neuroscience.

Early age conductive hearing loss causes audiogenic seizure and hyperacusis behavior.

Recent clinical reports found a high incidence of recurrent otitis media in children suffering hyperacusis, a marked intolerance to an otherwise ordinary environmental sound. However, it is unclear whether the conductive hearing loss caused by otitis media in early age will affect sound tolerance later in life. Thus, we have tested the effects of tympanic membrane (TM) damage at an early age on sound perception development in rats. Two weeks after the TM perforation, more than 80% of the rats showed audiogenic seizure (AGS) when exposed to loud sound (120 dB SPL white noise, < 1 min). The susceptibility of AGS lasted at least sixteen weeks after the TM damage, even the hearing loss recovered. The TM damaged rats also showed significantly enhanced acoustic startle responses compared to the rats without TM damage. These results suggest that early age conductive hearing loss may cause an impaired sound tolerance during development. In addition, the AGS can be suppressed by the treatment of vigabatrin, acute injections (250 mg/kg) or oral intakes (60 mg/kg/day for 7 days), an antiepileptic drug that inhibits the catabolism of GABA. c-Fos staining showed a strong staining in the inferior colliculus (IC) in the TM damaged rats, not in the control rats, after exposed to loud sound, indicating a hyper-excitability in the IC during AGS. These results indicate that early age conductive hearing loss can impair sound tolerance by reducing GABA inhibition in the IC, which may be related to hyperacusis seen in children with otitis media.

Grip force, EDL contractile properties, and voluntary wheel running after postdevelopmental myostatin depletion in mice.

There is no consensus about whether making muscles abnormally large by reducing myostatin activity affects force-generating capacity or the ability to perform activities requiring muscular endurance. We therefore examined grip force, contractile properties of extensor digitorum longus (EDL) muscles, and voluntary wheel running in mice in which myostatin was depleted after normal muscle development. Cre recombinase activity was induced to knock out exon 3 of the myostatin gene in 4-mo-old mice in which this exon was flanked by loxP sequences (Mstn[f/f]). Control mice with normal myostatin genes (Mstn[w/w]) received the same Cre-activating treatment. Myostatin depletion increased the mass of all muscles that were examined (gastrocnemius, quadriceps, tibialis anterior, EDL, soleus, triceps) by approximately 20-40%. Grip force, measured multiple times 2-22 wk after myostatin knockout, was not consistently greater in the myostatin-deficient mice. EDL contractile properties were determined 7-13 mo after myostatin knockout. Twitch force tended to be greater in myostatin-deficient muscles (+24%; P=0.09), whereas tetanic force was not consistently elevated (mean +11%; P=0.36), even though EDL mass was greater than normal in all myostatin-deficient mice (mean +36%; P<0.001). The force deficit induced by eccentric contractions was approximately twofold greater in myostatin-deficient than in normal EDL muscles (31% vs. 16% after five eccentric contractions; P=0.02). Myostatin-deficient mice ran 19% less distance (P<0.01) than control mice during the 12 wk following myostatin depletion, primarily because of fewer running bouts per night rather than diminished running speed or bout duration. Reduced specific tension (ratio of force to mass) and reduced running have been observed after muscle hypertrophy was induced by other means, suggesting that they are characteristics generally associated with abnormally large muscles rather than unique effects of myostatin deficiency.