BDNF rescues prefrontal dysfunction elicited by pyramidal neuron-specific DTNBP1 deletion in vivo

Abstract

Dystrobrevin-binding protein 1 (Dtnbp1) is one of the earliest identified schizophrenia susceptibility genes. Reduced expression of DTNBP1 is commonly found in brain areas of schizophrenic patients. Dtnbp1-null mutant mice exhibit abnormalities in behaviors and impairments in neuronal activities. However, how diminished DTNBP1 expression contributes to clinical relevant features of schizophrenia remains to be illustrated. Here, using a conditional Dtnbp1 knockout mouse line, we identified an in vivo schizophrenia-relevant function of DTNBP1 in pyramidal neurons of the medial prefrontal cortex (mPFC). We demonstrated that DTNBP1 elimination specifically in pyramidal neurons of the mPFC impaired mouse pre-pulse inhibition (PPI) behavior and reduced perisomatic GABAergic synapses. We further revealed that loss of DTNBP1 in pyramidal neurons diminished activity-dependent secretion of brain-derived neurotrophic factor (BDNF). Finally, we showed that chronic BDNF infusion in the mPFC fully rescued both GABAergic synaptic dysfunction and PPI behavioral deficit induced by DTNBP1 elimination from pyramidal neurons. Our findings highlight brain region- and cell type-specific functions of DTNBP1 in the pathogenesis of schizophrenia, and underscore BDNF restoration as a potential therapeutic strategy for schizophrenia.

Deletion of Dtnbp1 in mice impairs threat memory consolidation and is associated with enhanced inhibitory drive in the amygdala

“…This inconsistency between increased spine density without alterations of excitatory neurotransmission in Dys −/− mice, could be due to the increased proportion of thin, highly unstable spines, which do not normally make functional synapses 70 . However, we found that that the frequency of GABA A -receptor-mediated spontaneous IPSCs, but not their amplitude, was elevated in Dys −/− mice, which is consistent with the role dysbindin-1 plays in regulating GABA release 9,20 . The inhibition/excitation ratio was enhanced in neurons of Dys −/− mice, indicating that the activity of excitatory neurons could be inhibited in these animals.…”

“…The observed differences reinforce the view that the mutation effects may be brain region specific and be translated into region-specific functional modifications (e.g., distinct synaptic and neuronal changes). In the mPFC, impaired GABAergic transmission and fewer inhibitory synapses on pyramidal neurons of Dys −/− mice was apparently due to reduced activity-dependent secretion of brain-derived neurotrophic factor (BDNF) from pyramidal neurons 9,20 . Thus, in the BLA of Dys −/− mice, it is possible that BDNF release is increased from excitatory neurons, thereby enhancing BLA GABAergic transmission.…”

“…Dysbinin-1 is a coiled-coil-containing protein that serves diverse functions, including synaptic homeostasis, exocytosis, synaptic vesicle biogenesis, and dendritic spine formation 14–18 . Dys −/− mice exhibited impaired hippocampal long-term potentiation 19 , as well as disrupted excitatory and inhibitory synaptic transmission in the medial prefrontal cortex (mPFC) 9,20,21 . Additionally, abnormal dendritic morphology was found in hippocampal neurons in Dys −/− mice in vitro 15,22 .…”

Distinct and Dynamic ON and OFF Neural Ensembles in the Prefrontal Cortex Code Social Exploration

“…We previously demonstrated that GFP protein driven by CamKII promoter in AAV1 virus is mostly expressed in excitatory neurons (i.e., only 1% GFP positive neurons were GABAergic neurons) once being injected into mouse prelimbic cortex (Zhang et al, 2017). In this study, for calcium imaging experiments, we unilaterally injected AAV1.CamKII.GCaMP6f.WPRE.SV40 virus (University of Pennsylvania Vector Core, 500 nl with a titer of 2.76e13 GC/ml) into the dorsal region of the mouse prelimbic cortex, using the stereotactic coordinates (A/P: +1.9 mm, M/L: +0.3 mm, D/V: −1.7 mm).…”

Fluoxetine attenuates prepulse inhibition deficit induced by neonatal administration of MK-801 in mice

“…BDNF regulates neuronal proliferation, survival, and brain development, and represents a potentially relevant gene for schizophrenia [ 20 ]. Reduced expression of cerebral BDNF has been implicated in the pathophysiology of schizophrenia and has been considered to be related to the deficit of PPI, a behavioral endophenotype of schizophrenia [ 7 , 21 ]. There was an altered PPI of the acoustic startle response in an early postnatal hypoxia BDNF-deficient mouse model of schizophrenia [ 22 ].…”