PS231: Synaptic Plasticity & the Etiology of Schizophrenia

Training a Rat on a Spatial Memory Task Strengthens the Synaptic Connections Between CA3 and CA1 Pyramidal Neurons

• Following training on a spatial memory task, the synaptic connections between pyramidal neurons in the hippocampus become potentiated (in other words, they get stronger)

• At first, neuron A causes a small post synaptic potential (PSP) in neuron B (left), but over time if neuron A continues to simulate neuron B, the connection between them becomes strengthened such that the PSP is now larger (right) even with the same amount of stimulation—this phenomenon is known as long-term potentiation (LTP), a form of synaptic plasticity

• The million dollar question is, how does synaptic plasticity happen? It turns out there’s a few ways this phenomenon can occur, but we’ll focus on the most common way—LTP

Synaptic Plasticity

The biological process by which specific patterns of synaptic activity result in changes in synaptic strength thought to contribute to learning and memory

LTP

A form of synaptic plasticity wherein specific synapses are strengthened in an activitydependent manner within minutes—this strengthening of synapses is the physiological basis of learning and memory—this is what happens in our brain when we learn

Long-Term Potentiation (LTP) Strengthens Synaptic Connections Between Neurons (Physiological Changes)

Applying a brief burst (5s) of high frequency stimulation (100 Hz) onto the CA1 neuron causes a long-lasting, potentiated (stronger) response in the CA1 neuron—this is LTP

Long-Term Potentiation (LTP) is Mediated by AMPA and NMDA (Glutamate) Receptors

1. At first, glutamate activates only AMPARs, allowing Na+ influx

2. If enough Na+ flows in, the membrane becomes depolarized, which removes the Mg2+ block from NMDARs

3. This allows the influx of Na+ and Ca2+ though the NMDAR

4. Ca2+ then goes on activate proteins in the cell that traffic more AMPARs to the membrane, making the cell more excitable!

Long-Term Potentiation (LTP) Results From the Addition of More AMPA Receptors to the Postsynaptic Membrane

NMDAR activation leads to

1. more APMARs added to the post-synaptic membrane and

2. more glutamate release, which makes the connection stronger!

Over Longer Timescales, Regular Communication Between Neurons Can Lead to Structural Changes: the Formation of New Dendritic Spines

• In the long term (approx. few days), LTP can cause structural changes in neurons such as the growth of more dendritic spines—more synaptic connections!

• These structural changes take longer because they rely on activity-dependent changes in gene expression (e.g. actin scaffolding proteins to build new dendritic spines)

• This is yet another efficient way to make stronger connections between communicating neurons!

Review of Synaptic Plasticity: LTP Can Cause Physiological and (Eventually) Structural Changes in Neurons

• Left: In the short term (within minutes), LTP induces physiological changes in neurons (e.g. more NT release, more AMPARs, or both) that enhance/strengthen the synaptic connection between communicating neurons

• Right: In the long term (within a few days), LTP can cause structural changes in neurons such as the growth of more dendritic spines—more synaptic connections between communicating neurons = stronger connection!

Trephined skulls 5000 BCE

• Release of demons

• Belief that mental disorders due to evil spirits, etc.

Hippocrates (400 BCE) and Galen (2nd Century CE)

• Imbalance of body humors (fluids)

• Medical treatments designed to restore balance

• Galen: personalities

  • Shakespeare often described his characters in terms of the core humors

History of Psychopathology: “Lunatic Asylums”

• First: St Mary of Bethlehem

  • London, 1247

  • “Bedlam” for horrific practices and conditions

  • Funding: violent patients put on display for public; calmer patients sent to beg on streets

• Pite-Salpetriere Hospital

  • Paris, 1656

  • Mostly for women: prostitutes, mentally ill, or just poor

  • Prison

• Both hospitals still function today

Nineteenth century treatment for psychiatric disorders

• Rotational therapy: reduce brain congestion

• Benjamin Rush: tranquilizing chair

• Teeth removal to treat mental illness

• Hydrotherapy: lay in bathtub

Psychotic disorders

• Schizophrenia

• Delusional disorder

• Substance-induced psychotic disorder

Affective disorder

• Major depressive disorder

• Bipolar disorder

• Premenstrual dysphoric disorder

• Post-partum depression

Anxiety disorder

• Generalized anxiety disorder

• Social anxiety disorder

• Panic disorder

Schizophrenia

• Greek: schizen, “to split” and phren, “mind”

• This “splitting of the mind” however, does not refer to multiple personalities within the same individual (i.e. dissociative identity disorder, as is commonly misunderstood), but rather a disconnect between thought, emotion, and behavior—different aspects of a single personality

• In “psychotic disorders” such as schizophrenia, people experience psychoses: disturbances in thoughts and perceptions that result in a loss of touch with reality (e.g. delusions and hallucinations)

• Modern treatment usually consists of a combination of behavioral therapy and use of antipsychotic medications