The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia–neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS. We cover neuronal energy consumption in neural transmission and basic (‘housekeeping’) cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non‐neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS.

Highlights d Calcium channels are organized in transient nanodomains d Ca V 2.1 channel mobility influences synaptic vesicle release d C-terminal splicing of Ca V 2.1 alters association with synaptic vesicles d Transient channel-scaffold interactions are relevant for shortterm plasticity

Background: Cytosolic glutaredoxin 2 (Grx2) is essential for neuronal development in zebrafish; collapsin response mediator protein 2 (CRMP2) was identified as Grx2 substrate. Results: Oxidation of CRMP2 by hydrogen peroxide induces an intermolecular disulfide, changes in ␣-helical content, and hydrophobicity. Conclusion:The dithiol-disulfide redox switch defines two conformations of CRMP2. Significance: This switch may be functional during axonal outgrowth.

In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), which control the functions and mobility of synaptic receptors as well as the diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We showed that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM both in vivo and in vitro. ADAMTS immunoreactivity was detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We have outlined a molecular scenario of how synaptic activity and neuromodulation are linked to ECM rearrangements via increased cAMP levels, NMDA receptor activation, and intracellular calcium signaling.

VGCCs are multisubunit complexes that play a crucial role in neuronal signaling. Auxiliary a2d subunits of VGCCs modulate trafficking and biophysical properties of the pore-forming a1 subunit and trigger excitatory synaptogenesis. Alterations in the expression level of a2d subunits were implicated in several syndromes and diseases, including chronic neuropathic pain, autism, and epilepsy. However, the contribution of distinct a2d subunits to excitatory/inhibitory imbalance and aberrant network connectivity characteristic for these pathologic conditions remains unclear. Here, we show that a2d1 overexpression enhances spontaneous neuronal network activity in developing and mature cultures of hippocampal neurons. In contrast, overexpression, but not downregulation, of a2d3 enhances neuronal firing in immature cultures, whereas later in development it suppresses neuronal activity. We found that a2d1 overexpression increases excitatory synaptic density and selectively enhances presynaptic glutamate release, which is impaired on a2d1 knockdown. Overexpression of a2d3 increases the excitatory synaptic density as well but also facilitates spontaneous GABA release and triggers an increase in the density of inhibitory synapses, which is accompanied by enhanced axonal outgrowth in immature interneurons. Together, our findings demonstrate that a2d1 and a2d3 subunits play distinct but complementary roles in driving formation of structural and functional network connectivity during early development. An alteration in a2d surface expression during critical developmental windows can therefore play a causal role and have a profound impact on the excitatory-to-inhibitory balance and network connectivity.

It is a daily challenge for our brains to establish new memories via learning while providing stable storage of remote memories. In the adult vertebrate brain, bimodal regulation of the extracellular matrix (ECM) may regulate the delicate balance of learning-dependent plasticity and stable memory formation. Here, we trained adult male mice in a cortex-dependent auditory discrimination task and measured the abundance of ECM proteins brevican (BCN) and tenascin-R over the course of acquisition learning, consolidation, and long-term recall in two learning-relevant brain regions; the auditory cortex and hippocampus. Although early training led to a general downregulation of total ECM proteins, successful retrieval correlated with a region-specific and transient upregulation of BCN levels in the auditory cortex. No other parameter such as arousal or stress could account for the transient and region-specific BCN upregulation. This performance-dependent biphasic regulation of the ECM may assist transient plasticity to facilitate initial learning and subsequently promote the long-term consolidation of memory.

In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), controlling functions and mobility of synaptic receptors as well as diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We show that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM, in vivo and in vitro. ADAMTS immunoreactivity is detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We outline a molecular scenario how synaptic activity and neuromodulation are linked to ECM rearrangements via increased cAMP levels, NMDA receptor activation, and intracellular calcium signaling.