Cerebellum-Specific Deletion of the GABAA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior

Abstract

SUMMARY Granule cells (GCs) of the cerebellar input layer express high-affinity δ GABA A subunit-containing GABA A receptors (δGABA A Rs) that respond to ambient GABA levels and context-dependent neuromodulators like steroids. We find that GC-specific deletion of δGABA A (cerebellar [cb] δ knockout [KO]) decreases tonic inhibition, makes GCs hyperexcitable, and in turn, leads to differential activation of cb output regions as well as many cortical and subcortical brain areas involved in cognition, anxiety-like behaviors, and the stress response. Cb δ KO mice display deficits in many behaviors, but motor function is normal. Strikingly, δGABA A deletion alters maternal behavior as well as spontaneous, stress-related, and social behaviors specifically in females. Our findings establish that δGABA A Rs enable the cerebellum to control diverse behaviors not previously associated with the cerebellum in a sex-dependent manner. These insights may contribute to a better understanding of the mechanisms that underlie behavioral abnormalities in psychiatric and neurodevelopmental disorders that display a gender bias.

GluA4 facilitates cerebellar expansion coding and enables associative memory formation

“…To further assess the influence of inhibition on GC excitability, we analyzed gain and rheobase of the input-output relationship. Blocking inhibition increased the gain and reduced the rheobase current in WT ( Figure 2D ), consistent with previous studies ( Hamann et al, 2002 ; Rothman et al, 2009 ; Rudolph et al, 2020 ). By contrast, bicuculline had little effect on gain and rheobase in GluA4-KO GCs (ANOVA gain: genotype × drug: F = 4.24, p = 0.041, η 2 p = 0.028; rheobase: genotype × drug: F = 2.00, p = 0.16, η 2 p = 0.014; Figure 2D ), indicating that tonic inhibition is reduced in these mice.…”

“…Gain was calculated from linear fits to the input-output relationship. Average gain in WT was 4.3 ± 0.4 Hz (control, n = 36 GCs), in line with previous studies ( Gall et al, 2003 ; Rizwan et al, 2016 ; Rudolph et al, 2020 ; Soda et al, 2019 ; Straub et al, 2020 ). For display purposes, traces in figures were smoothed with a Savitzky-Golay second-order filter with a 25-point window size.…”

“…Persistent activation of δ- and α6-containing extrasynaptic GABA A Rs causes a tonic inhibitory conductance in cerebellar GCs ( Brickley et al, 2001 ; Hamann et al, 2002 ; Stell et al, 2003 ) that also influences their input-output relationship ( Figure 2—figure supplement 1 ; Mitchell and Silver, 2003 ; Rudolph et al, 2020 ). We directly investigated tonic inhibition by isolating inhibitory conductance and bath-applying bicuculline.…”

GluA4 enables associative memory formation by facilitating cerebellar expansion coding

“…Persistent activation of δ - and α 6-containing extrasynaptic GABA A Rs causes a tonic inhibitory conductance in cerebellar GCs (Brickley et al, 2001; Hamann et al, 2002; Stell et al, 2003) that also influences their excitability (Figure S2A–C; (Mitchell and Silver, 2003; Rudolph et al, 2020)). We directly investigated tonic inhibition by isolating inhibitory conductance in WT and GluA4-KO GCs and bath-applying bicuculline.…”

Abnormal Cerebellar Development in Autism Spectrum Disorders

“…For instance, recent work shows that Purkinje cell-specific deletion of tyrosine hydroxylase impairs behavioral flexibility and reduces social interest in a three-chamber assay [87]. In addition, granule cell-specific deletion of the δGABA A receptor subunits results in anxiety-like behavior as well as female-specific deficits in social behavior and maternal care [88]. It is important to note that gait and motor learning are not substantially affected in either of these manipulations.…”