Impacts of Perinatal Nicotine Exposure on nAChR Expression and Glutamatergic Synaptic Transmission in the Mouse Auditory Brainstem.

Exposure to nicotine in utero, often due to maternal smoking, significantly elevates the risk of auditory processing deficits in offspring. This study investigated the effects of chronic nicotine exposure during a critical developmental period on the functional expression of nicotinic acetylcholine receptors (nAChRs), glutamatergic synaptic transmission, and auditory processing in the mouse auditory brainstem. We evaluated the functionality of nAChRs at a central synapse and explored the impact of perinatal nicotine exposure (PNE) on synaptic currents and auditory brainstem responses (ABR) in mice. Our findings revealed developmentally regulated changes in nAChR expression in the medial nucleus of the trapezoid body (MNTB) neurons and presynaptic Calyx of Held terminals. PNE was associated with enhanced acetylcholine-evoked postsynaptic currents and compromised glutamatergic neurotransmission, highlighting the critical role of nAChR activity in the early stages of auditory synaptic development. Additionally, PNE resulted in elevated ABR thresholds and diminished peak amplitudes, suggesting significant impairment in central auditory processing without cochlear dysfunction. This study provides novel insights into the synaptic disturbances that contribute to auditory deficits resulting from chronic prenatal nicotine exposure, underlining potential targets for therapeutic intervention.

Heterogeneous complement and microglia activation mediates stress-induced synapse loss.

Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the mouse medial prefrontal cortex (mPFC). Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (ApoE high ) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the ApoE high microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases.

Brain-Derived Neurotrophic Factor Is Involved in Activity-Dependent Tonotopic Refinement of MNTB Neurons.

In the mammalian brain, auditory brainstem nuclei are arranged topographically according to acoustic frequency responsiveness. During postnatal development, the axon initial segment (AIS) of principal neurons undergoes structural refinement depending on location along the tonotopic axis within the medial nucleus of the trapezoid body (MNTB). However, the molecular mechanisms underlying the structural refinement of the AIS along the tonotopic axis in the auditory brainstem have not been explored. We tested the hypothesis that brain-derived neurotrophic factor (BDNF) is a molecular mediator of the structural development of the MNTB in an activity-dependent manner. Using BDNF heterozygous mutant (BDNF+/- ) mice, we examined the impact of global BDNF reduction on structural and functional development of MNTB neurons by assessing AIS structure and associated intrinsic neuronal properties. BDNF reduction inhibits the structural and functional differentiation of principal neurons along the tonotopic axis in the MNTB. Augmented sound input during the critical period of development has been shown to enhance the structural refinement of the AIS of MNTB neurons. However, in BDNF +/- mice, MNTB neurons did not show this activity-dependent structural modification of the AIS following repeated sound stimulation. In addition, BDNF+/- mice lacked a defined isofrequency band of neuronal activity following exposure to 16 kHz sound, suggesting degradation of tonotopy. Taken together, structural development and functional refinement of auditory brainstem neurons require physiological levels of BDNF to establish proper tonotopic gradients.

The endogenous neuronal complement inhibitor SRPX2 protects against complement-mediated synapse elimination during development.

Complement-mediated synapse elimination has emerged as an important process in both brain development and neurological diseases, but whether neurons express complement inhibitors that protect synapses against complement-mediated synapse elimination remains unknown. Here, we show that the sushi domain protein SRPX2 is a neuronally expressed complement inhibitor that regulates complement-dependent synapse elimination. SRPX2 directly binds to C1q and blocks its activity, and SRPX2-/Y mice show increased C3 deposition and microglial synapse engulfment. They also show a transient decrease in synapse numbers and increase in retinogeniculate axon segregation in the lateral geniculate nucleus. In the somatosensory cortex, SRPX2-/Y mice show decreased thalamocortical synapse numbers and increased spine pruning. C3-/-;SRPX2-/Y double-knockout mice exhibit phenotypes associated with C3-/- mice rather than SRPX2-/Y mice, which indicates that C3 is necessary for the effect of SRPX2 on synapse elimination. Together, these results show that SRPX2 protects synapses against complement-mediated elimination in both the thalamus and the cortex.

Antagonism of Neurotensin Receptors in the Ventral Tegmental Area Decreases Methamphetamine Self-Administration and Methamphetamine Seeking in Mice.

Background: Neurotensin is a peptide that modulates central dopamine neurotransmission and dopamine-related behaviors. Methamphetamine self-administration increases neurotensin levels in the ventral tegmental area, but the consequences for self-administration behavior have not been described. Here we test the hypothesis that antagonizing neurotensin receptors in the ventral tegmental area attenuates the acquisition of methamphetamine self-administration and methamphetamine intake. Methods: We implanted mice with an indwelling catheter in the right jugular vein and bilateral cannulae directed at the ventral tegmental area. Mice were then trained to nose-poke for i.v. infusions of methamphetamine (0.1 mg/kg/infusion) on a fixed ratio 3 schedule. Results: Mice receiving microinfusions of the neurotensin NTS1/NTS2 receptor antagonist SR142948A in the ventral tegmental area (10 ng/side) prior to the first 5 days of methamphetamine self-administration required more sessions to reach acquisition criteria. Methamphetamine intake was decreased in SR142948A-treated mice both during training and later during maintenance of self-administration. Drug seeking during extinction, cue-induced reinstatement, and progressive ratio schedules was also reduced in the SR142948A group. The effects of SR142948A were not related to changes in basal locomotor activity or methamphetamine psychomotor properties. In both SR142948A- and saline-treated mice, a strong positive correlation between methamphetamine intake and enhanced locomotor activity was observed. Conclusion: Our results suggest that neurotensin input in the ventral tegmental area during initial methamphetamine exposure contributes to the acquisition of methamphetamine self-administration and modulates later intake and methamphetamine-seeking behavior in mice. Furthermore, our results highlight the role of endogenous neurotensin in the ventral tegmental area in the reinforcing efficacy of methamphetamine, independent of its psychomotor effects.