The Role of Dcdc2 in Spike Timing and Glutamatergic Synaptic Transmission in Mouse Neocortex

Dyslexia is a phenotypically complex developmental disorder that involves significant impairment in reading fluency and/or accuracy, despite adequate intelligence and educational background. Variants in dyslexia-associated genes, including DCDC2, have been linked to altered neocortical activation, suggesting that they may play as of yet unspecified roles in neuronal physiology. In this study we explored changes in electrophysiological properties of excitatory neurons in a Dcdc2 mutant mouse model. We found elevated intrinsic excitability as a result of depolarized resting membrane potential in mutant neurons. Next, we measured decreased trial-to-trial temporal precision in spike trains elicited by either step currents or noise stimuli simulating synaptic inputs, independent from the change in excitability. NMDAR blockade was found effective in returning the heightened variability in spike timing back to wildtype levels, and we confirmed the presence of elevated NMDAR-mediated current, both tonic and phasic. We concluded that the decreased spike-time precision was a result of elevated NMDAR-mediated synaptic noise. These results are discussed in chapter 2. To identify the cause of increased NMDAR-mediated activities, we further tested a number of possible synaptic changes in Dcdc2 mutant layer 4 somatosensory cortex. We found that elevated presynaptic release probability, but not increase in postsynaptic glutamate receptor numbers or ambient glutamate levels, is responsible for excess postsynaptic excitatory activities. By blocking postsynaptic NMDARs first with hyperpolarization and MK-801, we showed that in the mutant enhanced presynaptic NMDAR function leads to higher release probability from presynaptic terminals. We further demonstrated that the increased preNMDAR function is present at layer 4-layer 4 connections, but not thalamus-layer 4 connections, at least for the evoked response-mediated preNMDAR activation. These findings are discussed in chapter 3. In summary, we demonstrated a preNMDAR-mediated increase in glutamate release in Dcdc2 mutant neurons, which then results in elevated synaptic noise and degraded spike-time precision in regular spiking neurons. These results demonstrate the first synaptic role of a dyslexia-associated gene, and reveal that Dcdc2 plays a role in restricting NMDAR, in particular preNMDAR function, within neocortical circuits