Mutation of the dyslexia-associated gene Dcdc2 impairs LTM and visuo-spatial performance in mice.

Developmental reading disorder (RD) affects 5-10% of school aged children, with a heritability of approximately 60%. Genetic association studies have identified several candidate RD susceptibility genes, including DCDC2; however, a direct connection between the function of these genes and cognitive or learning impairments remains unclear. Variants in DCDC2, a member of the doublecortin family of genes, have been associated in humans with RD and ADHD and Dcdc2 may play a role in neuronal migration in rats. In this study, we examined the effect of Dcdc2 mutation on cognitive abilities in mice using a visual attention and visuo-spatial learning and memory task. We show that both heterozygous and homozygous mutations of Dcdc2 result in persistent visuo-spatial memory deficits, as well as visual discrimination and long-term memory deficits. These behavioral deficits occur in the absence of neuronal migration disruption in the mutant mice, and may be comorbid with an anxiety phenotype. These are the first results to suggest a direct relationship between induced mutation in Dcdc2 and changes in behavioral measures. Dcdc2 mutant mice should prove useful in future studies designed to further dissect the underlying neural mechanisms that are impaired following Dcdc2 mutation.

Impaired detection of variable duration embedded tones in ectopic NZB/BINJ mice.

Utilizing rodent models, prior research has demonstrated a significant association between focal neocortical malformations (i.e. induced microgyria, molecular layer ectopias), which are histologically similar to those observed in human dyslexic brains, and rate-specific auditory processing deficits as seen in language impaired populations. In the current study, we found that ectopic NZB/BINJ mice exhibit significant impairments in detecting a variable duration 5.6 kHz tone embedded in a 10.5 kHz continuous background, using both acoustic reflex modification and auditory event-related potentials (AERP). The current results add further support to the association between focal cortical malformations and impaired auditory processing, and the notion that these auditory effects may occur regardless of the cortical location of the anomaly.

Electrophysiological and morphological characterization of neurons within neocortical ectopias.

Focal developmental abnormalities in neocortex, including ectopic collections of neurons in layer I (ectopias), have been associated with behavioral and neurological deficits. In this study, we used infrared differential interference contrast microscopy and whole cell patch-clamp to complete the first characterization of neurons within and surrounding neocortical ectopias. Current-clamp recordings revealed that neurons within ectopias display multiple types of action potential firing patterns, and biocytin labeling indicated that approximately 20% of the cells in neocortical ectopias can be classified as nonpyramidal cells and the rest as atypically oriented pyramidal cells. All cells had spontaneous excitatory (glutamatergic) and inhibitory (GABAergic) postsynaptic currents. Exhibitory postsynaptic currents consisted of both N-methyl-D-aspartate (NMDA) receptor-mediated and AMPA/kainate (A/K) receptor-mediated currents. The NMDA receptor-mediated component had decay time constants of 15.35 +/- 2.2 (SE) ms, while the A/K component had faster decay kinetics of 7.6 +/- 1.7 ms at -20 mV. GABA(A) receptor-mediated synaptic currents in ectopic cells reversed at potentials near the Cl- equilibrium potential and had decay kinetics of 16.65 +/- 1.3 ms at 0 mV. Furthermore we show that cells within ectopias receive direct excitatory and inhibitory input from adjacent normatopic cortex and can display a form of epileptiform activity.

Muscarinic receptors differentially modulate the persistent potassium current in striatal spiny projection neurons.

Cholinergic regulation of striatal spiny projection neuron activity is predominantly mediated through muscarinic receptor modulation of several subclasses of ion channels. Because of its critical role in governing the recurring episodes of hyperpolarization and depolarization characteristic of spiny neurons in vivo, the 4-aminopyridine-resistant, persistent potassium (K+) current, IKrp, would be a strategic target for modulation. The present results show that IKrp can be either suppressed or enhanced by muscarinic receptor stimulation. Biophysical analysis demonstrated that the depression of IKrp was associated with a hyperpolarizing shift in the voltage dependence of inactivation and a reduction in maximal conductance. By contrast, the enhancement of IKrp was linked to hyperpolarizing shifts in both activation and inactivation voltage dependencies. Viewed in the context of the natural activity of spiny neurons, muscarinic depression of IKrp should uniformly increase excitability in both hyperpolarized and depolarized states. In the hyperpolarized state, the reduction in maximal conductance should bolster the efficacy of impending excitatory input. Likewise, in the depolarized state, the decreased availability of IKrp produced by the shift in inactivation should enhance ongoing synaptic input. The alterations associated with enhancement of IKrp are predicted to have a more dynamic influence on spiny cell excitability. In the hyperpolarized state, the negative shift in activation should increase the flow of IKrp and attenuate subsequent excitatory synpatic input; whereas once the cell has traversed into the depolarized state, the negative shift in inactivation should reduce the availability of this current and diminish its influence on the existing excitatory barrage.

Biophysical characterization and functional consequences of a slowly inactivating potassium current in neostriatal neurons.

Neostriatal spiny projection neurons can display a pronounced delay in their transition to action potential discharge that is mediated by a slowly developing ramp depolarization. The possible contribution of a slowly inactivating A-type K+ current (IAs) to this delayed excitation was investigated by studying the biophysical and functional properties of IAs using whole cell voltage- and current-clamp recording from acutely isolated neostriatal neurons. Isolation of IAs from other voltage-gated, calcium-independent K+ currents was achieved through selective blockade of IAs with low concentrations (10 microM) of the benzazepine derivative, 6-chloro-7,8-dihydroxy-3-allyl- 1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepine (APB; SKF82958) and subsequent current subtraction. Examination of the voltage dependence of activation showed that IAs began to flow at approximately -60 mV in response to depolarization. The voltage dependence of inactivation revealed that approximately 50% of IAs channels were available at the normal resting potential (-80 mV) of these cells, but that only 20% of the channels were available at membrane potentials corresponding to spike threshold (about -40 mV). At these depolarized membrane potentials, the rate of activation was moderately rapid (tau approximately 60 ms), whereas the rate of inactivation was slow (tau approximately 1.5 s). The time course of removal of inactivation of IAs at -80 mV also was relatively slow (tau approximately 1.0 s). The subthreshold availability of IAs combined with its rapid activation and slow inactivation rates suggested that this current should be capable of dampening the onset of prolonged depolarizing responses, but over time its efficacy should diminish, slowly permitting the membrane to depolarize toward spike threshold. Voltage recording experiments confirmed this hypothesis by demonstrating that application of APB at a concentration (10 microM) that selectively blocks IAs substantially decreased the latency to discharge and increased the frequency of firing of neostriatal neurons. The properties of IAs suggest that it should play a critical role in placing the voltage limits on the recurring episodes of subthreshold depolarization which are characteristic of spiny neurons recorded in vivo. However, the voltage dependence and recovery kinetics of inactivation of IAs predict that its effectiveness will vary exponentially with the level and duration of hyperpolarization which precedes depolarizing episodes. Thus long periods of hyperpolarization should increase the availability of IAs and dampen succeeding depolarizations; whereas brief epochs of hyperpolarization should not sufficiently remove inactivation of IAs, thereby reducing its ability to limit subsequent depolarizing responses.