Neuronal Activity

Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase in the CDK family. It is expressed primarily in the central nervous system where it is activated when interacting with cofactors, p35 and p39. This protein regulates neuronal processes like synaptic plasticity, learning, and memory, making it critical in brain health and function. 

CDK5 regulation of synaptic plasticity is mediated largely by its influence on formation of dendritic spines where excitatory transmission takes place. CDK5 activity is associated with retraction of dendritic spines, resulting in tipping the balance away from long-term potentiation (LTP) and towards long-term depression (LDP), reducing synaptic strength over time (1). It appears to exert its effects in a multi-faceted manner, phosphorylating and modulating different proteins, such as N-methyl-d-aspartate (NMDA) receptors, in different contexts. NMDA receptors are critical regulators of synaptic plasticity due to their role in detecting coincident presynaptic and postsynaptic neuronal activity that leads to their activationand produces an influx of intracellular calcium that results in synaptic strengthening or weakening.

CDK5 also regulates other processes that contribute to synaptic plasticity, such as neurotransmitter release, while dysregulated CDK5 activity contributes to synaptic dysfunction and is implicated in neurodegenerative diseases and cognitive impairments. 

Dysregulation of CDK5 is associated with neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. One mechanism of dysregulation is via accumulation of p25, a cleaved form of CDK5 coactivator p35 that leads to hyperactivation and mislocalization of CDK5 (2).

Downstream effects of hyperactivation can include excessive neuronal autophagy, neuronal death and mitochondrial dysfunction driven by aberrant phosphorylation of CDK5 targets. As a specific example, hyperphosphorylation of tau protein and the associated formation of neurofibrillary tangles (NFTs) and neuronal death that are hallmarks of Alzheimer’s disease have been shown to be mediated by CDK5 hyperactivity in transgenic mice. Thus, targeting CDK5 may help to manage Alzheimer’s disease and other neurodegenerative disorders.

Long-term potentiation (LTP), a persistent increase in synaptic strength due to strong or frequent stimulation, is the most studied form of activity-dependent synaptic plasticity. It is triggered by the strong activation of N-methyl-d-aspartate receptors (NMDARs) in response to simultaneous glutamate binding and depolarization. 

These ligand-gated ion channels allow maximum influx of Ca²⁺, leading to increased intracellular Ca²⁺ levels that trigger signaling cascades involving a variety of protein kinases including calcium/calmodulin-dependent kinase II (CaMKII), cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs) (3).

The targets of these pathways mediate the structural changes in synapses and increased synaptic strength associated with LTP.

In association with its physiological role in memory formation and learning, LTP dysfunction as a result of aberrant NMDAR-mediated signaling can lead to impaired learning and memory loss and is implicated in Alzheimer’s disease.

Synaptic long-term depression (LTD) is a form of synaptic plasticity characterized by an activity-dependent and persistent decrease in synaptic strength. LTD works bidirectionally with LTP to normalize synaptic strength, create a stable and balanced memory mechanism and maintain neuronal homeostasis (3).

As synapses keep getting stronger because of LTP, they eventually reach a level where it is hard to encode and store new information. LTD selectively weakens specific synapses to make synaptic strengthening relevant and ensure that neural circuits remain flexible and responsive to new experiences, preventing overexcitation and maintaining homeostasis in the brain.  

Calcium signaling plays a critical role in synapse weakening or strengthening. LTP and LTD rely on NMDA-type glutamate receptor activation, which allows calcium ions to enter the postsynaptic cell, triggering a signaling cascade that results in synaptic weakening or potentiation. Small increases in calcium levels are observed in LTD, while high calcium influx results in potentiation.

High calcium entry leads to the activation of calcium–calmodulin–dependent protein kinase II (CaMKII). CaMKII translocates to the synapse and induces potentiation by phosphorylating subunits of AMPA-type glutamate receptors (4). On the other hand, small or moderate increases in calcium levels lead to calcium binding to calcineurin. Calcineurin triggers dephosphorylation events that lead to the removal of AMPA-type glutamate receptors, resulting in LTD.

Aberrant calcium signaling can lead to abnormal synaptic changes that result in neurological and neurodegenerative diseases like autism, schizophrenia, Parkinson’s disease and Huntington’s disease.

The movement of AMPA receptors (AMPARs) to and from the postsynaptic membrane is a crucial mechanism for changes in synaptic strength. LTD can occur with the removal of AMPARs from the synapses. However, the molecular mechanisms that underlie the removal of AMPARs in LTD are not fully understood (5). It is suggested that calcineurin can dephosphorylate AMPAR subunits, including GluA1 S845 and TARPs (6). This dephosphorylation event then leads to the removal of AMPA receptors from the membrane, resulting in decreased synaptic strength in LTD. 

CDK5 modulates neuronal events like synaptic plasticity, learning and memory by phosphorylating the NMDA receptor (NMDAR) subunit NR2B (7). This phosphorylation can modulate the receptor’s function, influencing calcium influx and other downstream signaling pathways involved in synaptic strength and plasticity. When CDK5’s regulation of NMDA receptors is impaired, it can potentially contribute to neurological disorders like schizophrenia and Alzheimer's disease.

Potential therapeutic approaches within the Cyclin-dependent kinase 5 (CDK5) pathway include inhibiting aberrant CDK5 activity, modulating its activator p25, and intervening in downstream signaling processes associated with neurodegenerative diseases such as tau phosphorylation.

By targeting these aspects of the CDK5 pathway, it may be possible to prevent or mitigate the neurotoxic events associated with diseases like Alzheimer's, offering new approaches for developing more effective treatment. For instance, a Cdk5 inhibitory peptide can prevent neuron loss and reduce tau hyperphosphorylation and inflammation (8). Regulating the activator of CDK5, p35, could restore synaptic function and reduce cognitive impairment.

Dendritic spines are tiny mushroom-like protrusions from dendrites that change in size and shape in response to neuronal activity. LTP and LTD influence their plasticity by altering their shape, size and number (1). During LTP, dendritic spines typically enlarge, reflecting the strengthened synaptic connection. Conversely, synaptic weakening in LTD is correlated to dendritic spine shrinkage or loss.