Early uneven ear input induces long-lasting differences in left-right motor function.

How asymmetries in motor behavior become established normally or atypically in mammals remains unclear. An established model for motor asymmetry that is conserved across mammals can be obtained by experimentally inducing asymmetric striatal dopamine activity. However, the factors that can cause motor asymmetries in the absence of experimental manipulations to the brain remain unknown. Here, we show that mice with inner ear dysfunction display a robust left or right rotational preference, and this motor preference reflects an atypical asymmetry in cortico-striatal neurotransmission. By unilaterally targeting striatal activity with an antagonist of extracellular signal-regulated kinase (ERK), a downstream integrator of striatal neurotransmitter signaling, we can reverse or exaggerate rotational preference in these mice. By surgically biasing vestibular failure to one ear, we can dictate the direction of motor preference, illustrating the influence of uneven vestibular failure in establishing the outward asymmetries in motor preference. The inner ear-induced striatal asymmetries identified here intersect with non-ear-induced asymmetries previously linked to lateralized motor behavior across species and suggest that aspects of left-right brain function in mammals can be ontogenetically influenced by inner ear input. Consistent with inner ear input contributing to motor asymmetry, we also show that, in humans with normal ear function, the motor-dominant hemisphere, measured as handedness, is ipsilateral to the ear with weaker vestibular input.

The Severity of Vestibular Dysfunction in Deafness as a Determinant of Comorbid Hyperactivity or Anxiety.

Attention-deficit/hyperactivity disorder (ADHD) and anxiety-related disorders occur at rates 2-3 times higher in deaf compared with hearing children. Potential explanations for these elevated rates and the heterogeneity of behavioral disorders associated with deafness have usually focused on socio-environmental rather than biological effects. Children with the 22q11.2 deletion or duplication syndromes often display hearing loss and behavioral disorders, including ADHD and anxiety-related disorders. Here, we show that mouse mutants with either a gain or loss of function of the T-Box transcription factor gene, Tbx1, which lies within the 22q11.2 region and is responsible for most of the syndromic defects, exhibit inner ear defects and hyperactivity. Furthermore, we show that (1) inner ear dysfunction due to the tissue-specific loss of Tbx1 or Slc12a2, which encodes a sodium-potassium-chloride cotransporter and is also necessary for inner ear function, causes hyperactivity; (2) vestibular rather than auditory failure causes hyperactivity; and (3) the severity rather than the age of onset of vestibular dysfunction differentiates whether hyperactivity or anxiety co-occurs with inner ear dysfunction. Together, these findings highlight a biological link between inner ear dysfunction and behavioral disorders and how sensory abnormalities can contribute to the etiology of disorders traditionally considered of cerebral origin.SIGNIFICANCE STATEMENT This study examines the biological rather than socio-environmental reasons why hyperactivity and anxiety disorders occur at higher rates in deaf individuals. Using conditional genetic approaches in mice, the authors show that (1) inner ear dysfunction due to either Tbx1 or Slc12a2 mutations cause hyperactivity; (2) it is vestibular dysfunction, which frequently co-occurs with deafness but often remains undiagnosed, rather than auditory dysfunction that causes hyperactivity and anxiety-related symptoms; and (3) the severity of vestibular dysfunction can predict whether hyperactivity or anxiety coexist with inner ear dysfunction. These findings suggest a need to evaluate vestibular function in hearing impaired individuals, especially those who exhibit hyperactive and anxiety-related symptoms.

Increased ß-catenin activity in the anterior neural plate induces ectopic mid-hindbrain characteristics.

BACKGROUND: The early telencephalon shares molecular features with the early mid-hindbrain region. In particular, these two developing brain areas each have a signaling center that secretes FGFs and an adjacent one that secretes WNTs. WNTs and FGFs each play essential roles in regulating cell fates in both the telencephalon and mid-hindbrain. Despite this similarity, telencephalic and mid-hindbrain precursors express distinct genes and ultimately generate different cell types, tissue morphologies, and neural functions. RESULTS: Here we show that genetically increasing the level of ß-catenin, a mediator of canonical WNT signaling, in the anterior neural plate causes a loss of telencephalic characteristics and a gain of mid-hindbrain characteristics. CONCLUSION: These results, together with previous ones demonstrating that increased WNT signaling in the anterior neural plate increases FGF expression, suggest that the levels of WNT and FGF signaling regulate telencephalic versus mid-hindbrain fates.

Paradoxical Hyperexcitability in Disorders of Neurodevelopment.

Autism Spectrum Disorder (ASD), Rett syndrome (RTT) and Angelman Syndrome (AS) are neurodevelopmental disorders (NDDs) that share several clinical characteristics, including displays of repetitive movements, developmental delays, language deficits, intellectual disability, and increased susceptibility to epilepsy. While several reviews address the biological basis of non-seizure-related ASD phenotypes, here, I highlight some shared biological mechanisms that may contribute to increased seizure susceptibility. I focus on genetic studies identifying the anatomical origin of the seizure phenotype in loss-of-function, monogenic, mouse models of these NDDs, combined with insights gained from complementary studies quantifying levels of synaptic excitation and inhibition. Epilepsy is characterized by a sudden, abnormal increase in synchronous activity within neuronal networks, that is posited to arise from excess excitation, largely driven by reduced synaptic inhibition. Primarily for this reason, elevated network excitability is proposed to underlie the causal basis for the ASD, RTT, and AS phenotypes. Although, mouse models of these disorders replicate aspects of the human condition, i.e., hyperexcitability discharges or seizures on cortical electroencephalograms, measures at the synaptic level often reveal deficits in excitatory synaptic transmission, rather than too much excitation. Resolving this apparent paradox has direct implications regarding expected outcomes of manipulating GABAergic tone. In particular, in NDDs associated with seizures, cortical circuits can display reduced, rather than normal or increased levels of synaptic excitation, and therefore suggested treatments aimed at increasing inhibition could further promote hypoactivity instead of normality. In this review, I highlight shared mechanisms across animal models for ASD, RTT, and AS with reduced synaptic excitation that nevertheless promote hyperexcitability in cortical circuits.

Increased Excitation-Inhibition Ratio Stabilizes Synapse and Circuit Excitability in Four Autism Mouse Models.

Distinct genetic forms of autism are hypothesized to share a common increase in excitation-inhibition (E-I) ratio in cerebral cortex, causing hyperexcitability and excess spiking. We provide a systematic test of this hypothesis across 4 mouse models (Fmr1-/y, Cntnap2-/-, 16p11.2del/+, Tsc2+/-), focusing on somatosensory cortex. All autism mutants showed reduced feedforward inhibition in layer 2/3 coupled with more modest, variable reduction in feedforward excitation, driving a common increase in E-I conductance ratio. Despite this, feedforward spiking, synaptic depolarization, and spontaneous spiking were largely normal. Modeling revealed that E and I conductance changes in each mutant were quantitatively matched to yield stable, not increased, synaptic depolarization for cells near spike threshold. Correspondingly, whisker-evoked spiking was not increased in vivo despite detectably reduced inhibition. Thus, elevated E-I ratio is a common circuit phenotype but appears to reflect homeostatic stabilization of synaptic drive rather than driving network hyperexcitability in autism.

A causative link between inner ear defects and long-term striatal dysfunction.

There is a high prevalence of behavioral disorders that feature hyperactivity in individuals with severe inner ear dysfunction. What remains unknown is whether inner ear dysfunction can alter the brain to promote pathological behavior. Using molecular and behavioral assessments of mice that carry null or tissue-specific mutations of Slc12a2, we found that inner ear dysfunction causes motor hyperactivity by increasing in the nucleus accumbens the levels of phosphorylated adenosine 3',5'-monophosphate response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase (pERK), key mediators of neurotransmitter signaling and plasticity. Hyperactivity was remedied by local administration of the pERK inhibitor SL327. These findings reveal that a sensory impairment, such as inner ear dysfunction, can induce specific molecular changes in the brain that cause maladaptive behaviors, such as hyperactivity, that have been traditionally considered exclusively of cerebral origin.