Brain‐derived neurotrophic factor haploinsufficiency impairs high‐frequency cortical oscillations in mice

Abstract

Schizophrenia is a complex psychiatric disorder with a heterogeneous aetiology involving genetic and environmental factors. Deficiencies in both brain-derived neurotrophic factor (BDNF) and NMDA receptor function have been implicated in the disorder and may play causal and synergistic roles. Perturbations in the regulation of electrophysiological signals, including high-frequency (γ: 30-80 Hz and β: 20-30 Hz) neuronal oscillations, are also associated with the disorder. This study investigated the influence of BDNF deficiency and NMDA receptor hypofunction on electrophysiological responses to brief acoustic stimuli. Adult BDNF heterozygote (BDNF ) and wild-type littermate C57Bl/6J mice were surgically implanted with EEG recording electrodes. All mice underwent EEG recording sessions to measure ongoing and auditory-evoked electrophysiological responses following treatment with MK-801 (0.3 mg/kg ip) or vehicle. Western blotting on post-mortem cortical tissue assessed parvalbumin and GAD67 expression - markers of interneurons which are involved in the generation of gamma oscillations. Compared with wild-type controls, BDNF mice exhibited markedly dampened electrophysiological responses to auditory stimuli, including reductions in the amplitude of multiple components of the event-related potential and auditory-evoked oscillations, as well as reduced ongoing cortical gamma oscillations. MK-801 elevated ongoing gamma power but suppressed evoked gamma power, and this was observed equally across genotypes. BDNF mice also displayed reductions in parvalbumin, but not GAD67 expression. We conclude that reduced BDNF expression leads to impairments in the generation of high-frequency neural oscillations, but this is not synergistic with NMDA receptor hypofunction. Reduced parvalbumin expression associated with BDNF haploinsufficiency may provide a molecular explanation for these electrophysiological deficits.

The mGluR2/3 agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice

“…Electrophysiologically, we observed a drug-induced increase in ongoing gamma and HFO power, along with a decrease in gamma power evoked by auditory stimuli, also in line with previous studies (Ehrlichman et al, 2009; Jones et al, 2014; Jones et al, 2018; Lee et al, 2017; Saunders et al, 2012). Treatment with MK-801 also increased gamma phase coherence between the mPFC and dHPC.…”

Impact of Chronic BDNF Depletion on GABAergic Synaptic Transmission in the Lateral Amygdala

“…Indeed, BDNF deficiency seems to especially affect parvalbumin and somatostatin/NPY-expressing interneurons in the cortex [40,48,49,50,51], and somatostatin/NPY-positive interneurons in the amygdala of female mice [52]. Interestingly, different subtypes of LA interneurons were reported to impose unitary IPSCs with unique features onto projection neurons, with stutter-firing interneurons showing the largest amplitudes of unitary IPSCs [53].…”

High-Frequency Neuronal Oscillatory Abnormalities in the Phospholipase C-β1 Knockout Mouse Model of Schizophrenia

“…To assess oscillatory activity, the raw ECoG signal was processed using a custom-written MATLAB script (v7.10.0, Natick, MA; The MathWorks, 2010). We extracted 2 primary outcomes from the data: ongoing oscillatory activity and event-related oscillatory activity elicited by the prepulse stimulus, as per our previous study (Jones et al, 2018). For the measurement of ongoing oscillations, the continuous raw ECoG data were sectioned into 2-second epochs and each epoch was subjected to Fast Fourier Transforms using the MATLAB pwelch function to calculate the Power Spectral Density estimate.…”