Shank3 Exons 14–16 Deletion in Glutamatergic Neurons Leads to Social and Repetitive Behavioral Deficits Associated With Increased Cortical Layer 2/3 Neuronal Excitability

Abstract

Shank3, an abundant excitatory postsynaptic scaffolding protein, has been associated with multiple brain disorders, including autism spectrum disorders (ASD) and Phelan-McDermid syndrome (PMS). However, how cell type-specific Shank3 deletion affects disease-related neuronal and brain functions remains largely unclear. Here, we investigated the impacts of Shank3 deletion in glutamatergic neurons on synaptic and behavioral phenotypes in mice and compared results with those previously obtained from mice with global Shank3 mutation and GABAergic neuron-specific Shank3 mutation. Neuronal excitability was abnormally increased in layer 2/3 pyramidal neurons in the medial prefrontal cortex (mPFC) in mice with a glutamatergic Shank3 deletion, similar to results obtained in mice with a global Shank3 deletion. In addition, excitatory synaptic transmission was abnormally increased in layer 2/3 neurons in mice with a global, but not a glutamatergic, Shank3 deletion, suggesting that Shank3 in glutamatergic neurons are important for the increased neuronal excitability, but not for the increased excitatory synaptic transmission. Neither excitatory nor inhibitory synaptic transmission was altered in the dorsal striatum of Shank3-deficient glutamatergic neurons, a finding that contrasts with the decreased excitatory synaptic transmission in global and Shank3-deficient GABAergic neurons. Behaviorally, glutamatergic Shank3-deficient mice displayed abnormally increased direct social interaction and repetitive self-grooming, similar to global and GABAergic Shank3-deficient mice. These results suggest that glutamatergic and GABAergic Shank3 deletions lead to distinct synaptic and neuronal changes in cortical layer 2/3 and dorsal striatal neurons, but cause similar social and repetitive behavioral abnormalities likely through distinct mechanisms.

IRSp53 Deletion in Glutamatergic and GABAergic Neurons and in Male and Female Mice Leads to Distinct Electrophysiological and Behavioral Phenotypes

“…Therefore, Irsp53 expression in glutamatergic neurons in the cortex, where Emx1 is strongly expressed, seems to be important for normal social interaction and locomotor activity. This is in line with the well-known importance of the PFC in the regulation of social cognition and interaction, previously reported in studies with human subjects as well as WT and mutant mice carrying ASD-and schizophrenia-related gene mutations (Ernst et al, 1997;Mundy, 2003;Pierce et al, 2004;Carper and Courchesne, 2005;Amodio and Frith, 2006;Gilbert et al, 2008;Rinaldi et al, 2008;Shalom, 2009;Courchesne et al, 2011;Yizhar et al, 2011;Testa-Silva et al, 2012;Liang et al, 2015;Barak and Feng, 2016;Ko, 2017;Selimbeyoglu et al, 2017;Cao et al, 2018;Pirone et al, 2018;Wang et al, 2018Wang et al, , 2019Guo et al, 2019;Lazaro et al, 2019;Phillips et al, 2019;Yoo et al, 2019). .…”

A DLG2 deficiency in mice leads to reduced sociability and increased repetitive behavior accompanied by aberrant synaptic transmission in the dorsal striatum

“…Increased self-grooming behavior in rodents is thought to represent pathological repetitive behavior (i.e., behavioral perseveration), which is one of the core symptoms of ASD [26]. Accordingly, animal models that display increased self-grooming behavior have been used to investigate the mechanisms underlying ASD symptoms [53][54][55]. It is well known that repetitive self-grooming behavior in rodents is strongly associated with dysfunction of the striatum [38,40].…”

Shifted Phase of EEG Cross-Frequency Coupling in Individuals with Phelan-McDermid Syndrome

“…Power was computed across frequencies using a three taper multitaper window (49). Power was then computed for a number of frequency bands: Delta [1-4 Hz), Theta [4-8 Hz), Alpha [8][9][10][11][12], Beta [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], and Gamma . Total power was computed as all frequencies between .…”