Cellular and circuit deficits in Fragile X syndrome

Fragile X syndrome (FXS) is the most common monogenic cause of autism, and multiple studies suggest a shared neurobiological basis of autism between FXS and other Autism Spectrum Disorders. We are interested in how changes in the functional expression of voltage-gated ion channels in mouse model of FXS alter synaptic integration and action potential firing in neurons of the hippocampus and prefrontal cortex. These interests encompass multiple projects.

Input-output transformation in a mouse model Fragile X syndrome. In cortical neurons, the transformation of synaptic inputs into action potential output requires three distinct neurophysiological processes: (1) dendritic integration of synaptic inputs, (2) the generation of local, non-linear dendritic events and (3) propagation and initiation of action potentials. We have evidence that synaptic integration and the subsequent generation of non-linear dendritic sodium and calcium spikes is impaired in CA1 and L5 PFC pyramidal neurons in FXS. We are currently investigating the underlying mechanisms and the functional consequences of this observation.

Cellular underpinnings of impaired social memory in Fragile X syndrome. Impairments of social memory and social behaviors are prominent in ASDs and FXS. The CA2 region of the hippocampus is critical for social memory. Specifically, long-term synaptic plasticity and neuromodulation by oxytocin is essential for the expression of social memory. We found that CA2 pyramidal neurons in Fmr1 knockout mice have reduced synaptic plasticity and are less responsive to oxytocin compared to wild type CA2 neurons. As part of an NIH award we are currently investigating the underlying cellular mechanism of these deficits.

Altered thalamocortical circuits in the Fmr1 KO mice. Changes in dendritic voltage-gated ion channels in PFC neurons alter how synaptic inputs from higher order thalamic nuclei are integrated and transformed into action potential output. We have data showing that the firing mode of PFC-targeting thalamocortical (TC) neurons is altered in Fmr1 KO mice. Optogenetic stimulation of TC inputs revealed that synaptic transmission from thalamic inputs onto L5 PFC dendrites is reduced, and nonlinear integration impaired, in Fmr1 KO TC circuits. We are using retrograde labeling to make targeted recordings from reciprocally connected TC neurons to determine how channelopathies affect TC circuits.

Changes in voltage-gated ion channel function in a model of tuberous sclerosis 

Tuberous sclerosis is a monogenic disorder that is caused by a loss-of-function mutation in the Tsc1 or Tsc2 genes. Neurological manifestations of tuberous sclerosis include neurodevelopmental delay, epilepsy, and TSC-associated neuropsychiatric disorders such as cognitive disability and autism spectrum disorder. A critical barrier to progress toward an effective treatment for tuberous sclerosis is that many of the cellular physiological mechanisms underlying tuberous sclerosis remain poorly understood. Despite their importance to controlling neuronal excitability, the pathophysiology of voltage-gated ion channels in tuberous sclerosis remains largely unknown.