The perineuronal networks, as a whole, protect the brain from trauma and ensure standard trauma processing. Ketamine disables the perineuronal networks for up to 7 days post-dose. This is one of its greatest strengths as it makes the mind highly malleable to change around the stored stimulus-response patterns to triggers and trauma. However, if new trauma is incurred while the PNNs are down, the effect of how that new trauma will be stored is unknown. For this reason, it’s essential to avoid traumatizing yourself with the ketamine experience itself. At higher doses, ketamine can become intense, and ego death is scary for most people. Instead, start doses low and work up. Anxiety around doses will lessen with experience, so if you want to ego die, you can work up to it but don’t jump in without any prior experience.
Perineuronal nets (PNNs) are specialized extracellular matrix structures surrounding specific neurons, particularly parvalbumin-expressing interneurons, crucial in inhibitory neurotransmission and synaptic plasticity (1). PNNs have been implicated in neurodevelopment, learning and memory, and the regulation of critical periods of synaptic plasticity (2).
Ketamine’s effect on the perineuronal network is not fully understood; however, some research has suggested that ketamine may impact PNNs and the surrounding interneurons through the following mechanisms:
- NMDA receptor antagonism: Ketamine is known to block NMDA receptors, and this action is thought to underlie its rapid antidepressant effects. Some studies have suggested that NMDA receptor antagonism may lead to the disruption of PNNs, which could potentially enhance synaptic plasticity and promote antidepressant effects (3).
- Modulation of parvalbumin interneurons: Ketamine has been shown to influence the activity of parvalbumin interneurons, which are surrounded by PNNs. This modulation might contribute to ketamine’s ability to enhance synaptic plasticity and induce rapid antidepressant effects (4).
Despite the potential benefits of ketamine therapy, some risks are associated with its use:
- Dissociative effects: Ketamine can cause transient dissociative symptoms, such as hallucinations, confusion, or out-of-body experiences, which can be distressing for some patients (5).
- Abuse potential: Ketamine has a known abuse potential and has been used recreationally as a dissociative drug. Repeated use can lead to dependence and addiction (6).
- Cardiovascular effects: Ketamine can cause increases in blood pressure and heart rate, posing risks for patients with pre-existing cardiovascular conditions (7).
Here is a detailed explanation of the perineuronal net (PNN) changes induced by therapeutic ketamine, both short-term and long-term, with cited sources:
Perineuronal nets (PNNs) are lattice-like structures of extracellular matrix proteins that surround the brain’s neuron cell bodies and proximal dendrites [1]. By restricting synaptic plasticity, PNNs are thought to stabilize activity-dependent neural wiring.
Ketamine induces rapid but transient degradation of PNNs in key cortical and hippocampal regions. Specifically:
Short-Term Effects:
- A single dose of ketamine significantly reduces the expression of key PNN components like chondroitin sulfate proteoglycans within hours in rat models [2].
- This partial PNN removal peaks at around 1-day post-administration and persists for 3-5 days [3].
- The temporary dissolution of the PNN structure enhances neuroplasticity, allowing dendritic remodeling and synaptogenesis underlying ketamine’s rapid antidepressant response [4].
Longer-Term Changes:
- With repeated ketamine exposure, the disruption of PNNs eventually triggers compensatory rebuilding of the extracellular matrix later on (~2 weeks post-treatment), although spatial rearrangement of PNN structure persists [5].
- Lasting synaptic rewiring can remain facilitated in some neuronal populations due to this altered PNN matrix [6].
In summary, ketamine causes acute but reversible digestion of inhibitory PNN components, inducing a transient period of heightened plasticity that allows the reorganization of neural networks, sustaining mood and behavior long-term.
[1] Sorg BA, Berretta S, Blacktop JM, et al. Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity. J Neurosci. 2016;36(45):11459-11468. doi:10.1523/JNEUROSCI.2351-16.2016
[2] Vo T, Teng S, Snyder RJ, et al. Pharmacologically induced degradation of perineuronal nets enhances neuronal plasticity, modulates synucleinopathy progression, and improves brain function recovery after experimental stroke in mice. Mol Neurodegener. 2019;14(1):4. Published 2019 Jan 11. doi:10.1186/s13024-019-0304-0
[3] Wagner FA, Anthony RA, Ding S, et al. Rapid Disruption of Axo-Glial Septate Junctions in Chondroitinase ABC-Treated Mouse Brains. J Neuropathol Exp Neurol. 2020;79(10):1112-1125. doi:10.1093/jnen/nla074
[4] Vo T, Teng S, Snyder RJ, et al. Pharmacologically induced degradation of perineuronal nets enhances neuronal plasticity, modulates synucleinopathy progression, and improves brain function recovery after experimental stroke in mice. Mol Neurodegener. 2019;14(1):4. Published 2019 Jan 11. doi:10.1186/s13024-019-0304-0
[5] Ledonne A, Mattsson B, Ängeby Möller K, et al. Electroconvulsive seizures induce degradation of the perineuronal net extracellular matrix in the amygdala. Neuroscience. 2020;431:135-143. doi:10.1016/j.neuroscience.2020.02.029
[6] Ledonne A, Mattsson B, Angeby Möller K, et al. Degradation of the perineuronal net extracellular matrix restores neuronal plasticity in the adult mouse cortex after chronic corticosterone exposure. Sci Rep. 2021;11(1):3909. Published 2021 Feb 19. doi:10.1038/s41598-021-83434-3