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    • Despite these data implicating Kdm b as a positive

    2021-10-12

    Despite these data implicating Kdm6b as a positive regulator of neuronal differentiation, and surprisingly, given the evidence that germline knockouts die perinatally due to an inability to breathe, the brains of Kdm6b knockout mice are remarkably normal in gross morphology [26,]. Interestingly, Kdm6b acts in postmitotic neurons to regulate synapse function. Burgold et al. [26] found that Kdm6b is required to maintain functionality of the Pre-Bötzinger complex (PBC), the neural pacemaker that controls the respiratory rhythm. In the absence of Kdm6b, although the neurons of the PBC are present, the circuit fails to functionally mature into a network state that can control proper breathing by the time of birth. Clues to the potential mechanisms of these circuit defects are suggested by studies of Kdm6b-dependent gene expression in developing cerebellar granule neurons (CGNs) []. CGN differentiation provides an effective means to identify gene expression that changes across the full-time course of differentiation including postmitotic stages of neuronal and synaptic maturation. Conditional knockout of Kdm6b in fate-committed CGN progenitors did not affect the expression of early neuronal marker genes and did not disrupt cerebellar morphology. However, the loss of Kdm6b expression did impair the late upregulation of gene products including specific GABA and glutamate receptor subunits that confer mature properties upon synaptic function []. These data are intriguing in light of the discovery of de novo KDM6B mutations in patients diagnosed with autism spectrum disorder (ASD), which is thought to be a primary disorder of synapses (Figure 2b) [28]. Finally, like LSD1n, Kdm6b is also implicated in activity-dependent gene regulation in the mature nervous system. However, unlike LSD1n, which likely acts in a constitutive manner to set the responsiveness of IEGs to synaptic stimuli, Kdm6b itself is a direct target of regulation by synaptic activity. Among all of the HDMs, the expression of Kdm6b is by far the most strongly induced by synaptic activity, showing over a 20-fold increase in mRNA expression in neurons of the hippocampus following pilocarpine-induced seizures [29]. Kdm6b is also induced in neurons of the prefrontal 5-Methoxy-UTP following cocaine exposure and withdrawal []. Whether there are direct synaptic activity-regulated targets of Kdm6b remains to be fully understood, although one study showed that pre-treatment of hippocampal neurons with the Kdm6b inhibitor GSK-J4 impaired NMDA-receptor dependent transcription of Brain-Derived Neurotrophic Factor (Bdnf) [31]. In hippocampal neurons Kdm6b is required for a form of synaptic activity-dependent survival called preconditioning. Surprisingly, in this context, Kdm6b is required for the induction of a program of inflammatory gene expression rather than traditional pro-survival genes like Bdnf [29]. These data raise the possibility that the pervasive function of Kdm6b in the control of inflammation [32] may also contribute to its cell-type specific functions in activity-dependent neuronal adaptations.
    Kdm5c: mutations in X-linked intellectual disability As mentioned above, targeted exome sequencing studies are rapidly revealing de novo mutations in a number of chromatin regulators associated with neurodevelopmental disorders including ID and ASD [33,34]. In addition, familial mutations in the H3K4-selective demethylase KDM5C (SMCX/JARID1C) have been identified as one of the more frequent causes of X-linked intellectual disability (XLID) (Figure 2c) [35]. In either case, the genetic association between any chromatin regulator and disease is only the beginning of the story, and recent efforts have focused on elucidating the cellular mechanisms that link chromatin dysregulation through gene expression and circuit formation to impaired brain function. Mice with germline deletion of Kdm5c recapitulate many of the cognitive, adaptive, and social abnormalities seen in patients with KDM5C mutations and, thus, offer a model for studying the neurological effects of Kdm5c disruption []. Behaviorally, Kdm5c knockout mice exhibit increased aggression, decreased anxiety, and impaired social behaviors as well as defects in learning and memory. At the cellular level, neurons in the knockout mice have defects in dendritic branching and spine morphology. Expression of disease-associated KDM5C mutations () in the Neuro2A cell line suppress retinoic acid-induced neurite growth, consistent with these point mutations being KDM5C loss-of-function at least for this cellular phenotype [37].