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Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with a multifarious clinical presentation. Even though many genetic risk factors have been identified and studied in mouse models, the neurophysiological mechanisms underlying the autistic phenotype are still unclear. Based on the high rates of comorbidity with epilepsy, it was hypothesized that the balance between excitation and inhibition in neural circuits may be disrupted in autistic individuals. In this dissertation, synaptic and network activity was measured in three different genetically modified mouse models that exhibit the characteristic behavioral abnormalities of the disorder: the Neurobeachin (Nbea) haploinsufficient mouse, the Neuroligin-3 (Nlgn3) knockout (KO) mouse, and the Neuroligin-4 (Nlgn4) KO mouse. Each of the affected proteins is involved in the formation and/or function of synapses in the central nervous system. Therefore, it was posited that the reduction or deletion of these proteins might alter the balance of excitatory to inhibitory synaptic transmission in individual neurons and in neural circuits. Extracellular recordings in the hippocampal dentate gyrus of anesthetized mice revealed that the excitation-inhibition (E-I) balance was reduced in Nbea haploinsufficient and Nlgn4 KO mice, but unchanged in Nlgn3 KO mice despite a reduction in excitatory synaptic transmission to dentate granule cells. Unexpectedly, the intrinsic excitability of dentate granule cells was altered in all three mouse models. These results imply that a homeostatic increase in the intrinsic excitability is able to compensate for the decreased excitatory transmission in Nlgn3 KO mice, whereas the decreased intrinsic excitability in the Nbea haploinsufficient and Nlgn4 KO mice leads to a reduction in the E-I balance. Taken together, these findings suggest that the influence of genetic factors on the E-I balance might be a potential common mechanism underlying the development of ASD., Autismus-Spektrum-Störung (ASS) ist eine häufig vorkommende neurologische Entwicklungsstörung mit einem mannigfaltigen klinischen Erscheinungsbild. Obwohl schon viele genetische Risikofaktoren identifiziert und in Mausmodellen untersucht worden sind, sind die neurophysiologischen Mechanismen, die zu einer Ausbildung eines autistischen Phänotyps führen, immer noch unklar. Basierend auf der hohen Komorbiditätsrate von ASS und Epilepsie wurde die Hypothese aufgestellt, dass das Gleichgewicht zwischen der Exzitation und Inhibition in neuronalen Netzwerken der betroffenen Personen gestört sein könnte. In dieser Dissertation wurde die Aktivität von Neuronen im Netzwerk und an der Synapse in drei genetisch veränderten Mausmodellen, die charakteristische Verhaltensauffälligkeiten der autistischen Störung aufzeigen, untersucht: im Neurobeachin (Nbea) haploinsuffizienten, im Neuroligin-3 (Nlgn3) Knock-out (KO), und im Nlgn4 KO Mausmodell. Diese Proteine sind alle an der Synapsenbildung und/oder -funktion im zentralen Nervensystem beteiligt. Daher wurde vermutet, dass die Reduktion oder Deletion dieser Proteine die Balance zwischen exzitatorischer und inhibitorischer synaptischer Übertragung in einzelnen Neuronen sowie in neuronalen Netzwerken ändern könnte. Extrazelluläre Ableitungen im hippocampalen Gyrus dentatus von anästhesierten Mäusen haben gezeigt, dass das Exzitations-Inhibitions(E-I)-Gleichgewicht in Nbea haploinsuffizienten sowie Nlgn4 KO-Mäusen reduziert war, aber in Nlgn3 KO-Mäusen trotz einer Verminderung der exzitatorischen synaptischen Übertragung unverändert war. Unerwarteterweise war die intrinsische Erregbarkeit der Körnerzellen in allen drei Mausmodellen verändert. Diese Ergebnisse weisen darauf hin, dass eine homöostatische Erhöhung der intrinsischen Erregbarkeit die Reduktion der exzitatorischen synaptischen Transmission in Nlgn3 KO-Mäusen kompensieren kann, wohingegen die verminderte intrinsische Erregbarkeit in Nbea haploinsuffizienten sowie Nlgn4 KO-Mä

Neuroligin-3 (Nlgn3), a neuronal adhesion protein implicated in autism spectrum disorder (ASD), is expressed at excitatory and inhibitory postsynapses and hence may regulate neuronal excitation/inhibition balance. To test this hypothesis, we recorded field excitatory postsynaptic potentials (fEPSPs) in the dentate gyrus of Nlgn3 knockout (KO) and wild-type mice. Synaptic transmission evoked by perforant path stimulation was reduced in KO mice, but coupling of the fEPSP to the population spike was increased, suggesting a compensatory change in granule cell excitability. These findings closely resemble those in neuroligin-1 (Nlgn1) KO mice and could be partially explained by the reduction in Nlgn1 levels we observed in hippocampal synaptosomes from Nlgn3 KO mice. However, unlike Nlgn1, Nlgn3 is not necessary for long-term potentiation. We conclude that while Nlgn1 and Nlgn3 have distinct functions, both are required for intact synaptic transmission in the mouse dentate gyrus. Our results indicate that interactions between neuroligins may play an important role in regulating synaptic transmission and that ASD-related neuroligin mutations may also affect the synaptic availability of other neuroligins.

The hippocampal dentate gyrus plays a role in spatial learning and memory and is thought to encode differences between similar environments. The integrity of excitatory and inhibitory transmission and a fine balance between them is essential for efficient processing of information. Therefore, identification and functional characterization of crucial molecular players at excitatory and inhibitory inputs is critical for understanding the dentate gyrus function. In this minireview, we discuss recent studies unraveling molecular mechanisms of excitatory/inhibitory synaptic transmission, long-term synaptic plasticity, and dentate granule cell excitability in the hippocampus of live animals. We focus on the role of three major postsynaptic proteins localized at excitatory (neuroligin-1) and inhibitory synapses (neuroligin-2 and collybistin). In vivo recordings of field potentials have the advantage of characterizing the effects of the loss of these proteins on the input-output function of granule cells embedded in a network with intact connectivity. The lack of neuroligin-1 leads to deficient synaptic plasticity and reduced excitation but normal granule cell output, suggesting unaltered excitation-inhibition ratio. In contrast, the lack of neuroligin-2 and collybistin reduces inhibition resulting in a shift towards excitation of the dentate circuitry.

Dendrites form predominantly binary trees that are exquisitely embedded in the networks of the brain. While neuronal computation is known to depend on the morphology of dendrites, their underlying topological blueprint remains unknown. Here, we used a centripetal branch ordering scheme originally developed to describe river networks—the Horton-Strahler order (SO)–to examine hierarchical relationships of branching statistics in reconstructed and model dendritic trees. We report on a number of universal topological relationships with SO that are true for all binary trees and distinguish those from SO-sorted metric measures that appear to be cell type-specific. The latter are therefore potential new candidates for categorising dendritic tree structures. Interestingly, we find a faithful correlation of branch diameters with centripetal branch orders, indicating a possible functional importance of SO for dendritic morphology and growth. Also, simulated local voltage responses to synaptic inputs are strongly correlated with SO. In summary, our study identifies important SO-dependent measures in dendritic morphology that are relevant for neural function while at the same time it describes other relationships that are universal for all dendrites.