Behavioral Neuroscience publications

Background: Sensory impairments commonly occur in patients with autism or intellectual disability. Fragile X syndrome (FXS) is one form of intellectual disability that is often comorbid with autism. In electroencephalographic (EEG) recordings obtained from humans with FXS, the ability of cortical regions to consistently synchronize, or "phase-lock", to modulated auditory stimuli is reduced compared to that of typically developing individuals. At the same time, less time-locked, "non-phase-locked" power induced by sounds is higher. The same changes occur in the Fmr1 knockout (KO) mouse - an animal model of FXS. We determined if Fmr1 deletion in a subset of brainstem auditory neurons plays any role in these EEG changes in the mouse. Methods: We reinstated FMRP expression in a subpopulation of brainstem auditory neurons in an otherwise Fmr1 KO control (conditional on; cON Fmr1) mouse and used EEG recordings to determine if reinstatement normalized, or "rescued", the phase-locking phenotype observed in the cON Fmr1 mouse. In determining rescue, this also meant that Fmr1 deletion in the same neuron population was necessary for the phenotype to occur. Results: We find that Fmr1 reinstatement in a subset of brainstem neurons rescues certain aspects of the phase-locking phenotype but does not rescue the increase in non-phase-locked power. Unexpectedly, not all electrophysiological phenotypes observed in the Fmr1 KO were observed in the cON Fmr1 mouse used for the reinstatement experiments, and this was likely due to residual expression of FMRP in these Fmr1 KO controls. Conclusions: Fmr1 deletion in brainstem neurons is necessary for certain aspects of the decreased phase-locking phenotype in the Fmr1 KO, but not necessary for the increase in non-phase-locked power induced by a sound. The most likely brainstem structure underlying these results is the inferior colliculus. We also demonstrate that low levels of FMRP can rescue some EEG phenotypes but not others. This latter finding provides a foundation for how symptoms in FXS individuals may vary due to FMRP levels and that reinstatement of low FMRP levels may be sufficient to alleviate particular symptoms.

Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.