Mechanisms of GABAergic and cholinergic neurotransmission in auditory thalamus: Impact of aging.

Age-related hearing loss is a complex disorder affecting a majority of the elderly population. As people age, speech understanding becomes a challenge especially in complex acoustic settings and negatively impacts the ability to accurately analyze the auditory scene. This is in part due to an inability to focus auditory attention on a particular stimulus source while simultaneously filtering out other sound stimuli. The present review examines the impact of aging on two neurotransmitter systems involved in accurate temporal processing and auditory gating in auditory thalamus (medial geniculate body; MGB), a critical brain region involved in the coding and filtering of auditory information. The inhibitory neurotransmitter GABA and its synaptic receptors (GABAARs) are key to maintaining accurate temporal coding of complex sounds, such as speech, throughout the central auditory system. In the MGB, synaptic and extrasynaptic GABAARs mediate fast phasic and slow tonic inhibition respectively, which in turn regulate MGB neuron excitability, firing modes, and engage thalamocortical oscillations that shape coding and gating of acoustic content. Acoustic coding properties of MGB neurons are further modulated through activation of tegmental cholinergic afferents that project to MGB to potentially modulate attention and help to disambiguate difficult to understand or novel sounds. Acetylcholine is released onto MGB neurons and presynaptic terminals in MGB activating neuronal nicotinic and muscarinic acetylcholine receptors (nAChRs, mAChRs) at a subset of MGB afferents to optimize top-down and bottom-up information flow. Both GABAergic and cholinergic neurotransmission is significantly altered with aging and this review will detail how age-related changes in these circuits within the MGB may impact coding of acoustic stimuli.

Strategy for genetic testing in Charcot-Marie-disease.

BACKGROUND: Charcot Marie Tooth disease (CMT) affects one in 2500 people. Genetic testing is often pursued for family planning purposes, natural history studies and for entry into clinical trials. However, identifying the genetic cause of CMT can be expensive and confusing to patients and physicians due to locus heterogeneity. METHODS: We analyzed data from more than 1000 of our patients to identify distinguishing features in various subtypes of CMT. Data from clinical phenotypes, neurophysiology, family history, and prevalence was combined to create algorithms that can be used to direct genetic testing for patients with CMT. FINDINGS: The largest group of patients in our clinic have slow motor nerve conduction velocities (MNCV) in the upper extremities. Approximately 88% of patients in this group have CMT1A. Those who had intermediate MNCV had primarily CMT1X (52.8%) or CMT1B (27.8%). Patients with very slow MNCV and delayed walking were very likely to have CMT1A (68%) or CMT1B (32%). No patients with CMT1B and very slow MNCV walked before 15 months of age. Patients with CMT2A form our largest group of patients with axonal forms of CMT. INTERPRETATION: Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we created a series of algorithms to guide testing. A more detailed review of this data is published in Annals of Neurology (1).

MFN2 mutations cause severe phenotypes in most patients with CMT2A.

BACKGROUND: Charcot-Marie-Tooth disease type 2A (CMT2A), the most common form of CMT2, is caused by mutations in the mitofusin 2 gene (MFN2), a nuclear encoded gene essential for mitochondrial fusion and tethering the endoplasmic reticulum to mitochondria. Published CMT2A phenotypes have differed widely in severity. METHODS: To determine the prevalence and phenotypes of CMT2A within our clinics we performed genetic testing on 99 patients with CMT2 evaluated at Wayne State University in Detroit and on 27 patients with CMT2 evaluated in the National Hospital for Neurology and Neurosurgery in London. We then preformed a cross-sectional analysis on our patients with CMT2A. RESULTS: Twenty-one percent of patients had MFN2 mutations. Most of 27 patients evaluated with CMT2A had an earlier onset and more severe impairment than patients without CMT2A. CMT2A accounted for 91% of all our severely impaired patients with CMT2 but only 11% of mildly or moderately impaired patients. Twenty-three of 27 patients with CMT2A were nonambulatory prior to age 20 whereas just one of 78 non-CMT2A patients was nonambulatory after this age. Eleven patients with CMT2A had a pure motor neuropathy while another 5 also had profound proprioception loss. MFN2 mutations were in the GTPase domain, the coiled-coil domains, or the highly conserved R3 domain of the protein. CONCLUSIONS: We find MFN2 mutations particularly likely to cause severe neuropathy that may be primarily motor or motor accompanied by prominent proprioception loss. Disruption of functional domains of the protein was particularly likely to cause neuropathy.