Table 1 Hypothetical link between the risk genes and proteins involved in schizophrenia and their pathophysiology, clinical outcomes and both ongoing and future treatments currently under investigation.

From: Glutamate and microglia activation as a driver of dendritic apoptosis: a core pathophysiological mechanism to understand schizophrenia

Risk genes /proteins involved

Pathophysiology

Clinical implications

Outcome

Therapeutic implications

SYNAPTIC PLASTICITY (PSD95, ARC complex, actin and other cytoskeletal proteins of the dendritic spines)

Aberrant circuitry

LTD and LTP failure for learning and memory

Inability to form new synapses

Negative and cognitive symptoms

Negative

Drugs promoting the formation of dendritic spines and preventing their loss (intranasal peptide davunetide –AL-108-; estrogens such as raloxifene; clozapine?)

NMDA (GRIN2A) and AMPA (GRIA1) GLUTAMATE RECEPTORS

Disrupted excitatory-inhibitory balance

Regionally-located glutamate storm-apoptosis and synaptic overpruning in PFC and HPC

Disrupted brain gamma-oscillations contributing to negative and cognitive symptoms

Gray matter loss (CT, MRI)

High levels of glutamate (1H-MRS) associated with poor outcome and treatment resistance

Negative

Modulators of GABAergic system

Attenuation of glutamate release by inhibitors of VGSC (Evenamide (NW-3509A))

AMPA Modulators (Ampakine CX516)

Anti-glutamatergic drugs modulating metabotropic mGlu2/3 receptor

Antiapoptotic effects of SGAPs?

Inhibitors of caspase-3 (Q-VD-OPh; Z-VAD-fmk)*

Blockers of cytochrome c release of the mitochondrial apoptotic pathway*

VDCC (CACNA1C)

Calcium overload-apoptosis and synaptic overpruning

Gray matter loss (CT, MRI)

Negative

Calcium channel antagonists?

IMMUNE SYSTEM (MHC and proteins of the complement system: C1q,C3,C4)

Contributes to apoptosis and synaptic overpruning via microglial activation

Gray matter loss (CT, MRI)

Negative

Drugs targeting microglia activation such as minocycline or other drugs blocking microglial phagocytic receptors

DRD2

Contributes to the downstream mesostriatal dopamine dysregulation

Aberrant salience

Positive psychotic symptoms (sub-threshold in prodromal stage; first-episode psychosis and relapses)

Increased dopamine transmission (PET, SPECT)

Dopamine overreactivity after amphetamine administration

Positive/Negative (TRS)

Current antipsychotic drugs blocking dopamine D2 receptors

New drugs regulating dopamine function (synthesis, vesicular storage, dopamine D2 autoreceptors)**

  1. AMPA: alfa-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; ARC: activity-regulated cytoskeleton-associated protein; CACNA1C: calcium voltage-gated channel subunit alpha 1C; CT: computerized tomography; DRD2: dopamine receptor D2; GABA: gamma-aminobutyric acid; HPC: hippocampus; LTD: Long-term depression; LTP: Long-term potentiation; MCH: major histocompatibility complex; MRI: magnetic resonance imaging; NMDA: N-methy-D-aspartate; PET: positron emission tomography; PFC: prefrontal cortex; PSD: post-synaptic density protein; SGAPs: second-generation antipsychotics; SPECT: single photon emission computerized tomography; TRS: treatment-resistant schizophrenia; VDCC: voltage-dependent calcium channel; VGSC: voltage-gated sodium channel; 1H-MRS: magnetic resonance spectroscopy.
  2. *Only investigated in preclinical studies in animal models of some classic neurodegenerative disorders.
  3. **For a recent review see Kaar and colleagues131.
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