Cellular-Specific Therapeutic Targeting of Inhibitory Circuits in Fragile X Syndrome
Molly Huntsman, PhD
Co-Principal Investigator
Christian Cea-Del Rio, PhD
Co-Principal Investigators
University of Colorado
Denver, CO
Summary
Studies have shown that the function of inhibitory networks is disturbed in Fragile X syndrome. This abnormality is not well understood but appears to be secondary to abnormalities in metabotropic glutamate and endocannabinoid systems.
With a $90,000 grant from FRAXA, Dr. Molly Huntsman’s team examined how these networks interact and how inhibitory deficits can best be remedied.
The Results
Brain Development in Fragile X Mice is Corrected by Activating PKCε
Dr. Banerjee and his team discovered that protein kinase C epsilon (PKCε) is under-expressed in key brain areas involved in social and emotional behavior in Fragile X mice. They studied the effects of PKCε suppression in the hippocampal CA1 region. When they stimulated PKCε during early development using a drug, they were able to correct social behavior deficits and anxiety seen later in life. This study suggests that early postnatal PKCε-mediated signaling regulates brain wiring responsible for social behavior and anxiety.
The team's findings, PKC epsilon as a neonatal target to correct FXS-linked AMPA receptor translocation in the hippocampus, boost PVN oxytocin expression, and normalize adult behavior in Fmr1 knockout mice, were published in PubMed on April 1, 2021.
The Science
Cognitive function depends on synaptic information processing and integration in neuronal networks at specified frequencies. Though behavioral phenotypes vary, many neurological disorders with marked cognitive abnormalities such as Fragile X syndrome (FXS), epilepsy and schizophrenia all share dysfunction of neuronal excitatory and inhibitory balance, and synchronization. Cortical inhibitory interneurons control the excitability of neuronal populations and determine the synchronization of excitatory networks at specified frequencies. Fragile X mouse models show alterations in both excitatory and inhibitory neurotransmission, but the impacts of dysfunctional inhibitory neuronal circuits that control brain networks are largely unexplored.
Our previous work reveals abnormalities in the ability of the somatostatin-positive (Sst) low threshold spiking (LTS) interneuron to synchronize cortical networks in Fmr1 KO mice (Paluszkiewicz et al., 2011) – specifically through altered activation of metabotropic glutamate receptors (mGluRs). Our present work now shows that Sst-LTS interneurons fail to undergo an mGluR-dependent and endocannabinoid-mediated phenomenon called slow-self inhibition (SSI) in Fmr1 KO mice. We hypothesize that the synthesis of endocannabinoids is altered in Fragile X syndrome and disrupts the capabilities of the Sst-LTS interneurons to function. This failure of Sst interneurons to control their own excitability through faulty endocannabinoid mobilization results in inadequate control of synchronization and network properties. Our goal is to determine the specific roles of the Sst-LTS interneuron populations in the somatosensory cortical circuit and how rescuing deficient cell properties in the network will affect the mouse model phenotype.
Grant Post Revisions
- 2021/04 - Added The Results.
- 2013/06 - Original grant post published.
