Studies have shown that the function of inhibitory networks is disturbed in Fragile X. 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 in 2013-2014, Dr. Molly Huntsman’s team examined how these networks interact and how inhibitory deficits can best be remedied.
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.