Animal Models of Schizophrenia Notes

Symptom Domains: * Positive: Hallucinations, delusions, and disordered thought. * Negative: Anhedonia, social withdrawal, loss of emotion, and poverty of thought/speech. * Cognitive: Impaired executive function, memory deficits, and reduced attention span.
Causes: A combination of genetic factors (DISC1, NRG1, dysbindin, reelin) and environmental stressors (substance abuse, maternal stress, social isolation).
Research Methods: Clinical studies utilize GWAS (Genome-wide association studies), neuroimaging (fMRI, PET), and post-mortem analyses. Preclinical studies employ mouse models for genetic and environmental risk factors.

Prepulse Inhibition (PPI): Measures sensorimotor gating. It is the weakening of a startle reflex to a pulse when preceded by a weaker prepulse. * Calculation: $\text{\%PPI} = (\frac{\text{pulse alone} - \text{prepulse}}{\text{pulse alone}}) \times 100$
Radial Arm Maze: Evaluates spatial learning and working memory. Errors are recorded when an animal revisits an arm.
Social Interaction Tests: Used to measure sociability and response to social novelty.
Other Tests: Elevated plus maze (anxiety) and Open field test (exploration).

Neonatal Ventral Hippocampal Lesion (VH): * Excitotoxic lesion using ibotenic acid during the critical period of $P7-8$ . * Phenotype appears post-puberty: includes PPI deficits, reduced sociability, and decreased $\text{GAD67 mRNA}$ in the PFC.
Genetic Models: * DISC1 (Disrupted in Schizophrenia 1): An intracellular scaffold protein. Mutants show reduced dendritic growth, enlarged lateral ventricles, and PPI deficits reversible by antipsychotics (HLP and CLZ). * NRG1 (Neuregulin 1): Involved in myelination and neurotransmission. Mutants (NRG1+/-) show increased aggression and decreased social novelty preference. CLZ reverses locomotor hyperactivity.

Glutamate Hypothesis: Postulates NMDA receptor hypofunction. NMDA antagonists like PCP (phencyclidine) and ketamine induce SZ symptoms. NR1 KO mice exhibit social isolation and hyperactivity.
Dopamine Theory (Amphetamine): Models positive symptoms (hyperactivity, PPI deficits) via increased mesolimbic activity. * Dosage: $1-5\,mg/kg$ ( $3 \times$ daily).
Maternal Immune Activation: Mimicked using Poly(I:C) (a $dsRNA$ molecule). Infection in the first trimester increases risk $7\text{-fold}$ .
Environmental Models: * Post-weaning social isolation: Results in neophobia and hyperactivity. * Gestational MAM (methylazoxymethanol): Administered at $GD17$ , leading to post-puberty PPI deficits.

Construct Validity: Difficulty in modeling complex human psychiatric traits in rodents.
Complexity: Addressing gene-gene and gene-environment interactions.
Symptom Targeting: The need for better models specifically for negative and cognitive domains, as current treatments primarily target positive symptoms.