A sound-driven cortical phase-locking change in the Fmr1 KO mouse requires Fmr1 deletion in a subpopulation of brainstem neurons

Validating brain activity measures as reliable indicators of individual diagnostic group and genetically mediated sub-group membership Fragile X Syndrome

“…In fact, a number of studies in the fmr1 KO mouse both in vivo and in vitro have narrowed the focus for circuit and molecular level understanding of biologic contributors to both resting and chirp EEG ndings in FXS. In particular, studies in which fmr1 was conditionally knocked-out in excitatory cells in forebrain cortex [17] and inferior colliculus [19] have begun to dissociate features of the chirp EEG to subcorticallymediated synchronization de cits that are then inherited by auditory cortex from cortically-driven gamma power enhancements. Cortically mediated gamma power enhancement is also supported mechanistically by ndings of enhanced synchronization between layers 2/3 and 5 in auditory cortex, indicating that local cortical circuits are hyperexcitable in the gamma frequency range [29], whereas subcortical structures drive exibility to changing task demands such as those presented by the linearly changing synchronization frequency in the chirp task [19].…”

“…In particular, studies in which fmr1 was conditionally knocked-out in excitatory cells in forebrain cortex [17] and inferior colliculus [19] have begun to dissociate features of the chirp EEG to subcorticallymediated synchronization de cits that are then inherited by auditory cortex from cortically-driven gamma power enhancements. Cortically mediated gamma power enhancement is also supported mechanistically by ndings of enhanced synchronization between layers 2/3 and 5 in auditory cortex, indicating that local cortical circuits are hyperexcitable in the gamma frequency range [29], whereas subcortical structures drive exibility to changing task demands such as those presented by the linearly changing synchronization frequency in the chirp task [19]. Resting power abnormalities in FXS may re ect similar mechanisms for gamma power enhancement [16,30] or may re ect thalamic or hippocampal inhibitory de cits via changes to cross-frequency coupling between theta, alpha and gamma power [9,12,31].…”

“…Additionally, sensory abnormalities measured via EEG including neural oscillatory synchronization to an auditory chirp stimulus are conserved across species [13] [14] and show small molecule target engagement in FMR1 KO mice [8, [15][16]. Further, preclinical models have highlighted speci c cell types [17,18]and brain structures [19] that may underlie these auditory chirp oscillatory abnormalities, and thus may serve as good targets for pharmacological intervention. Additional preclinical work has suggested that these phenotypes are speci c to the auditory modality [20], further narrowing the eld of inquiry to manageable outcomes.…”

Dysfunction of specific auditory fibers impacts cortical oscillations, driving an autism phenotype despite near‐normal hearing

“…(i) Reduced LFP power in Bdnf Pax2 KO mice: The elevated spontaneous LFP activity in Bdnf Pax2 KO mice is comparable to EEG recordings from individuals with Fragile X Syndrome, the leading inherited cause of autism. 60 Recordings in the correspondent Fmr1 KO mouse also revealed reduced evoked LFPs to sound stimuli along with enhanced induced and spontaneous LFP activity. [60][61][62] In Bdnf Pax2 KO mice, these findings could be linked to an elevated excitatory baseline activity at the thalamocortical input (Graphic Abstract iii).…”

“…60 Recordings in the correspondent Fmr1 KO mouse also revealed reduced evoked LFPs to sound stimuli along with enhanced induced and spontaneous LFP activity. [60][61][62] In Bdnf Pax2 KO mice, these findings could be linked to an elevated excitatory baseline activity at the thalamocortical input (Graphic Abstract iii). Typically, in a feed-forward mode of function, LFP power in layer IV is defined by thalamocortical input activity, which transmits the input activity of layer IV to infragranular layer V-VI (output) by a large and early current sink into the supragranular layers I-III.…”