Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants of BdnfPax2KOs causes severe cognitive disabilities. In BdnfPax2KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here: Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus (DCN) brainstem neurons in otherwise nearly normal hearing BdnfPax2KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism.

Age-related decoupling of auditory nerve fibers from hair cells (cochlear synaptopathy) has been linked to temporal processing deficits and impaired speech recognition performance. The link between both is elusive. We have previously demonstrated that cochlear synaptopathy, if centrally compensated through enhanced input/output function (neural gain), can prevent age-dependent temporal discrimination loss. It was also found that central neural gain after acoustic trauma was linked to hippocampal long-term potentiation (LTP) and upregulation of brain-derived neurotrophic factor (BDNF). Using middle-aged and old BDNF-live-exon-visualization (BLEV) reporter mice we analyzed the specific recruitment of LTP and the activity-dependent usage of Bdnf exon-IV and -VI promoters relative to cochlear synaptopathy and central (temporal) processing. For both groups, specimens with higher or lower ability to centrally compensate diminished auditory nerve activity were found. Strikingly, low compensating mouse groups differed from high compensators by prolonged auditory nerve latency. Moreover, low compensators exhibited attenuated responses to amplitude-modulated tones, and a reduction of hippocampal LTP and Bdnf transcript levels in comparison to high compensators. These results suggest that latency of auditory nerve processing, recruitment of hippocampal LTP, and Bdnf transcription, are key factors for age-dependent auditory processing deficits, rather than cochlear synaptopathy or aging per se.

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Deep brain stimulation (DBS) has evolved as a promising alternative treatment for Parkinson’s disease (PD), but the underlying mechanisms remain poorly understood. Moreover, conventional DBS protocols targeted at basal ganglia sites can turn out completely ineffective for some PD patients, warranting the search for alternative targets. The inferior colliculus (IC) is a midbrain auditory relay station involved in sensorimotor processes. High-frequency 2500 Hz electrical stimulation of the IC elicits escape behaviour and interferes with haloperidol-induced catalepsy in rats, a state reminiscent of Parkinsonian akinesia, but clinical implication is limited since the protocol is aversive. However, typical DBS stimulation frequencies range between 20–180 Hz. We therefore tested the effects of a low-frequency 30 Hz-DBS protocol on haloperidol-induced catalepsy and aversive behaviour in rats. We show that low-frequency 30 Hz-DBS targeted at the IC strongly ameliorates haloperidol-induced catalepsy without any evidence of stimulation-induced escape behaviour. Furthermore, 30 Hz-DBS of the IC produced no place avoidance in a place conditioning paradigm and induced no anxiety-related behaviour on the elevated plus maze, indicating that the protocol has no aversive or anxiogenic side effects. Our findings provide first evidence that the IC can serve as an alternative, non-conventional DBS target.