A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development

Abstract

Multiple genetic factors related to autism spectrum disorder (ASD) have been identified, but the biological mechanisms remain obscure. Timothy syndrome (TS), associated with syndromic ASD, is caused by a gain‐of‐function mutation, G406R, in the pore‐forming subunit of L‐type Ca2+ channels, Cav1.2. In this study, a mouse model of TS, TS2‐neo, was used to enhance behavioral phenotyping and to identify developmental anomalies in inhibitory neurons. Using the IntelliCage, which enables sequential behavioral tasks without human handling and mouse isolation stress, high social competitive dominance was observed in TS2‐neo mice. Furthermore, histological analysis demonstrated inhibitory neuronal abnormalities in the neocortex, including an excess of smaller‐sized inhibitory presynaptic terminals in the somatosensory cortex of young adolescent mice and higher numbers of migrating inhibitory neurons from the medial ganglionic eminence during embryonic development. In contrast, no obvious changes in excitatory synaptic terminals were found. These novel neural abnormalities in inhibitory neurons of TS2‐neo mice may result in a disturbed excitatory/inhibitory (E/I) balance, a key feature underlying ASD.

The CaV1.2 G406R mutation decreases synaptic inhibition and alters L-type Ca2+ channel-dependent LTP at hippocampal synapses in a mouse model of Timothy Syndrome

“…The even larger decrease in sIPSC frequency in TS2-neo mice, which we were able to at least in part link to decreased presynaptic GABA release, could be related to decreased retrograde communication from CA1 pyramidal cells to presynaptic interneurons via brain-derived neurotrophic factor, an activity-dependent gene product whose expression is known to be controlled by LTCC-dependent transcriptional signaling and to regulate presynaptic GABAergic properties and E/I balance ( Belfield et al, 2006 ; Greer and Greenberg, 2008 ; Guzikowski and Kavalali, 2022 ; Peng et al, 2010 ; Singh et al, 2006 ). In addition, studies in TS2-neo mice and iPSC-derived cerebral organoids from patients with TS have both identified impairments in cortical interneuron migration that could also contribute to decreased inhibition ( Birey et al, 2022 ; Horigane et al, 2020 ). Thus, we cannot rule out additional direct contributions of Ca V 1.2 G406R mutant expression in presynaptic interneurons.…”

Loss of Cav1.2 channels impairs hippocampal theta burst stimulation-induced long-term potentiation

“…By contrast, here we used thealpha-CamK2 promoter, which is not activated until postnatal day 18 [42]. Since Ca v 1.2calcium signaling is a critical regulator of early neuronal, dendritic and synaptic development [43][44][45][46][47], very early elimination of Ca v 1.2 via theNexpromoter could lead to developmental adaptations that might allow sufficient synaptic strengthening for the maturation of the embryonic brain necessary for viability. This adaptation could then result in an adult brain deficient in Ca v 1.2that is still able to execute TBS-induced LTP.…”

L-type calcium channels and neuropsychiatric diseases: Insights into genetic risk variant-associated genomic regulation and impact on brain development

“…While the impact of loss of Cacna1c (Ca v 1.2) on neurogenesis is unknown, given that the expression of Cacna1c is weak in the VZ throughout mouse embryonic development (see Panagiotakos et al, 2019 [ 116 ] for E11, 14, 16, and postnatal day (P)1 and Horigane et al, 2020 [ 124 ] for E17) in which the neural progenitors reside, it is likely that loss of Cacna1c (Ca v 1.2) would not impact neurogenesis. Interestingly, male mice and rats with heterozygous loss of Cacna1c or male mice with Cacna1c loss in excitatory cells show reduced adult neurogenesis in the hippocampus [ 31 , 100 , 125 , 126 ].…”