Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission

Abstract

Shrm4, a protein expressed only in polarized tissues, is encoded by the KIAA1202 gene, whose mutations have been linked to epilepsy and intellectual disability. However, a physiological role for Shrm4 in the brain is yet to be established. Here, we report that Shrm4 is localized to synapses where it regulates dendritic spine morphology and interacts with the C terminus of GABAB receptors (GABABRs) to control their cell surface expression and intracellular trafficking via a dynein-dependent mechanism. Knockdown of Shrm4 in rat severely impairs GABABR activity causing increased anxiety-like behaviour and susceptibility to seizures. Moreover, Shrm4 influences hippocampal excitability by modulating tonic inhibition in dentate gyrus granule cells, in a process involving crosstalk between GABABRs and extrasynaptic δ-subunit-containing GABAARs. Our data highlights a role for Shrm4 in synaptogenesis and in maintaining GABABR-mediated inhibition, perturbation of which may be responsible for the involvement of Shrm4 in cognitive disorders and epilepsy.

TSPAN5 Enriched Microdomains Provide a Platform for Dendritic Spine Maturation through Neuroligin-1 Clustering

“…Primary hippocampal neurons were prepared from either Wistar E18 rat brains (Folci et al, 2014;Valnegri et al, 2011;Zapata et al, 2017) or C57BL/6 P0 mice. Neurons were plated onto coverslips coated overnight with 0.25 mg ml À1 poly-D-lysine (Sigma Aldrich) at 75,000 per well and grown in Neurobasal medium supplemented with 2% B27 (prepared as in Chen et al 2008), 0.25% L-glutamine, 1% penicillin/streptomycin and 0.125% Glutamate (Sigma Aldrich).…”

Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking

“…In addition to its well-known functions as a stress-induced protein (Ameri and Harris, 2008), a number of studies have implicated ATF4 in synaptic plasticity and in learning and memory. Depending on cellular context, ATF4 has been characterized as either an inhibitor or promoter of synaptic plasticity (Pasini et al, 2015). Similarly divergent suggestions about ATF4's functions in learning and memory have been advanced, but these are largely based on indirect and nonselective manipulation of ATF4 activity or expression (Chen et al, 2003;Costa-Mattioli et al, 2007).…”

“…To probe directly ATF4's role in normal brain function, we have monitored the consequences of its knockdown or knock-out in neuronal culture and in animals. This has led to observations that ATF4 plays a role in regulation of mushroom dendritic spine density as well as in synaptic glutamatergic function (Liu et al, 2014). These effects appeared to be due to ATF4's direct transcriptional regulation of RhoGDI␣ (product of the Arhgdia gene), which in turn affects stability of the Rho family member Cdc42 that is involved in regulation of the actin cytoskeleton (Pasini et al, 2016).…”

“…This has led to observations that ATF4 plays a role in regulation of mushroom dendritic spine density as well as in synaptic glutamatergic function (Liu et al, 2014). These effects appeared to be due to ATF4's direct transcriptional regulation of RhoGDI␣ (product of the Arhgdia gene), which in turn affects stability of the Rho family member Cdc42 that is involved in regulation of the actin cytoskeleton (Pasini et al, 2016). At the physiological level, loss of ATF4 manifested in reduced frequency and amplitude of mEPSCs, followed by defective LTP and LTD as well as in memory deficits (Pasini et al, 2015).…”

Sema7A, a brain immune regulator, regulates seizure activity in PTZ‐kindled epileptic rats

“…Two weeks after lentivirus injection, each group was given a daily dose of PTZ (35 mg/kg, ip,), and behavioral changes were accessed. Rats with grade 4 or 5 seizures were selected for behavioral studies, and the latency to the first seizure, number of seizures, and total duration of seizures were separately recorded …”