Postsynaptic FMRP Promotes the Pruning of Cell-to-Cell Connections among Pyramidal Neurons in the L5A Neocortical Network

Abstract

Pruning of structural synapses occurs with development and learning. A deficit in pruning of cortical excitatory synapses and the resulting hyperconnectivity is hypothesized to underlie the etiology of fragile X syndrome (FXS) and related autistic disorders. However, clear evidence for pruning in neocortex and its impairment in FXS remains elusive. Using simultaneous recordings of pyramidal neurons in the layer 5A neocortical network of the wild-type (WT) mouse to observe cell-to-cell connections in isolation, we demonstrate here a specific form of "connection pruning." Connection frequency among pyramidal neurons decreases between the third and fifth postnatal weeks, indicating a period of connection pruning. Over the same interval in the FXS model mouse, the Fmr1 knock-out (KO), connection frequency does not decrease. Therefore, connection frequency in the fifth week is higher in the Fmr1 KO compared with WT, indicating a state of hyperconnectivity. These alterations are due to postsynaptic deletion of Fmr1. At early ages (2 weeks), postsynaptic Fmr1 promoted the maturation of cell-to-cell connections, but not their number. These findings indicate that impaired connection pruning at later ages, and not an excess of connection formation, underlies the hyperconnectivity in the Fmr1 KO mouse. FMRP did not appear to regulate synapses individually, but instead regulated cell-to-cell connectivity in which groups of synapses mediating a single cell-to-cell connection are uniformly removed, retained, and matured. Although we do not link connection pruning directly to the pruning of structurally defined synapses, this study nevertheless provides an important model system for studying altered pruning in FXS.

Synapse-type-specific plasticity in local circuits

“…Furthermore, activity levels must be kept within reasonable bounds, and it is likely that one or several interneuron types specifically adjust their inhibitory influence according to key developmental events such as eye opening, or in pathological states such as physical trauma, inflammation, or epilepsy. Indeed, STSP dysfunction has been observed in a variety of disease states ranging from schizophrenia [74], Alzheimer's disease [75], to autism spectrum disorders [76,77], demonstrating that an understanding of the properties of STSP may be fundamental to treating neurological diseases.…”

Postsynaptic mGluR5 promotes evoked AMPAR-mediated synaptic transmission onto neocortical layer 2/3 pyramidal neurons during development

“…We also performed an additional analysis of these connectivity frequencies where the four genotypic pre/post combinations were sorted into two groups based on pre-or postsynaptic Cre expression. This type of merging has been performed in previous studies using pre/post recordings (Hanson and Madison 2007;Patel et al 2014). Again, postsynaptic Grm5 deletion decreased connectivity frequency (Fig.…”

“…Interestingly, our unexpected finding that AMPAR-mediated evoked transmission is weakened with Grm5 deletion in light of the known role of mGluR5 in LTD is analogous to a paradox in synaptic phenotypes in the Fragile X model mouse, the Fmr1 KO. In this mouse, there is enhanced acutely induced Gp1 mGluR-dependent long-term depression, but at the same time, there is increased synapse number and connectivity in the Fmr1 KO (Bagni and Greenough 2005;Bear et al 2004;Huber et al 2002;Patel et al 2014). These contradicting phenotypes may both be due to enhanced mGluR5 signaling (Bear et al 2004;Dolen et al 2007).…”

Melatonin as an Interventional Novel Candidate for the Individual with Autistic Fragile X Syndrome in Human

“…These distinct features are related with impaired synaptic signaling and connection. The disruption of excitatory synapse pruning and hyper connectivity is primarily found in FXS patients and the Fmr1 KO mouse due to loss of post synaptic FMRP [111]. A deficit of FMRP resulting in this incomplete pruning induces cell to cell hyper connections in synapses.…”